Methods of treating leukemia using cytotoxicity targeting chimeras for CCR2-expressing cells

Abstract

The present disclosure relates to methods of treating leukemia using a heterobifunctional molecule, referred to as a cytotoxicity targeting chimera (CyTaC) or antibody recruiting molecule (ARM), that is able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein.

Description

[0001] METHODS OF TREATING LEUKEMIA USING CYTOTOXICITY TARGETING CHIMERAS FOR CCR2-EXPRESSING CELLS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 716,025, filed November 4, 2024, and United States Provisional Patent Application serial number 63 / 675,043, July 24, 2024; the contents of each of which are hereby incorporated by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically via Patent Center in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 23, 2025, is named 220049_seqlist.xml and is 15,192 bytes in size. FIELD OF THE DISCLOSURE The present disclosure relates to methods of treating leukemia using a heterobifunctional molecule, referred to as a cytotoxicity targeting chimera (CyTaC) or antibody recruiting molecule (ARM), that is able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. BACKGROUND Cell-surface proteins and their ligands play key roles in a range of inflammatory, infectious, and autoimmune diseases, as well as tumor initiation, growth and metastasis. Antibody-based therapeutics have promising properties as drug candidates for these indications due to their selectivity for pathogenic cell-surface targets and their ability to direct immune surveillance to target-expressing tissues or cells to induce depletion of the pathogenic cells. Examples of such depletion mechanisms include antibody-dependent cellular cytotoxicity (ADCC), antibody- dependent cellular phagocytosis (ADCP), and complement-dependant cytotocity (CDC). However, antibody-based therapeutics often suffer from a lack of bioavailability, high cost, thermal instability, and difficult manufacturing due to their size, complexity and peptide based structures. Conversely, small molecule therapeutics often provide affordability, stability, and the convenience of oral dosing, but may suffer from poor selectivity and off-target effects, while also lacking the immune control of therapeutic antibodies. Accordingly, a need exists for improved therapeutic approaches that target pathogenic cells for use in the treatment of disease. Such therapeutic methods are provided in the present disclosure. SUMMARY The present disclosure relates to methods of treating leukemia using a heterobifunctional molecule, referred to as a cytotoxicity targeting chimera (CyTaC) or antibody recruiting molecule (ARM), that is able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. One aspect of the disclosure provides a method of treating a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a heterobifunctional compound described herein, such as a compound of Formula I, and an anti-cotinine antibody, or antigen-binding fragment thereof, to thereby treat the leukemia. Another aspect of the disclosure provides a method of depleting C-C motif chemokine receptor 2 (CCR2)-expressing cells in a patient suffering from a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a heterobifunctional compound described herein, such as a compound of Formula I, and an anti- cotinine antibody, or antigen-binding fragment thereof. Also provided herein are pharameutical compositions and anti-cotinine antibodies for use in the therapeutic methods. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a Kaplan-Meier survival curve of patients with high and low CCR2 expression. Patients expressing CCR2 at levels of the 85th percentile or greater were defined as high expressers (186 patients). Patients expressing CCR2 at levels of the 15th percentile or lower were defined as low expressers (186 patients). FIG.2 is a Kaplan-Meier survival curve of patients with high and low CCR2 expression. Patients expressing CCR2 at levels of the 85th percentile or greater were defined as high expressers (186 patients). Patients expressing CCR2 at levels of the 15th percentile or lower were defined as low expressers (186 patients). FIG.3 provides a summary of Cox Proportional Hazards model fit. FIG.4 shows a gating strategy on human pathological cells within AML PBMCs. Briefly, human PBMCs were identified via FSC-A x SSC-A. Live PBMCs were identified via SSC-A xV500-C-A. Pathological cells (PCs) were identified via SSC-A x BV605 (CD45) and defined asmononuclear cells, excluding red blood cells and lymphocytes. CD14 expression was confirmed via SSC-A x PE-CD14 and CCR2 expression was confirmed via SSC-A x APC. FIG. 5 is a graph showing percent of pathological cells expressing CCR2 from donor samples having <20% monocytes, 20-40% monocytes or >40% monocytes. FIG.6 is a graph showing a summary of CCR2 positive cells in an entire cohort of patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). FIG.7 shows a gating strategy on human CMML PBMCs. Briefly, human PBMCs were identified via FSC-A x SSC-A. Live PBMCs were identified via SSC-H x APC-H (Cell Trace FarRed). CD45+ cells were identified via FSC-H x FITC-H. CD14+ cells were identified via FSC-H xPC7-H. CCR2 expression was identified via FSC-H x PE-A. FIG.8 is a graph showing percent of CD14+ expressing monocytes within CD45+ immune cell populations of CMML donors. Secondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. FIG.9 is a graph showing percentage of CCR2 expressing cells within CD14+ monocyte population of CMML donors. Secondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. ND: not determined; CCR2 expression was not assessed by flow cytometry for Donor 1. FIG.10 is a graph showing percent CD14+ monocyte depletion among CMML donors in the presence of S,S-cotinine carboxamide antibody and CCR2-CyTaC.εSecondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. FIG.11 is a graph showing percent CCR2+ monocyte depletion among CMML donors in the presence of S,S-cotinine carboxamide antibody and CCR2-CyTaC.εSecondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. ND: not determined; CCR2 staining was not performed on Donor 1. FIG.12A is a heatmap representing the AUC for the CCR2-CyTAC dose-response in the CD45 / CD11b double positive population, comparing results in the absence and presence of heterologous NK cells. FIG. 12B is a graph showing CCR2-CyTAC platform activity (AUCinv) across the CD45 / CD11b double positive population of all the patients in the cohort (n=18). FIG.13A is a heatmap of CCR2-CyTAC activity over total PCs. FIG. 13B is a boxplot comparing treatment activity on PCs. p-value = 0.0152. *Corresponds to CMML samples. FIG.14 is a graph showing percent cell killing by Test Article across different cell types, as further described in Example 8. FIG.15 is a graph showing percent cell killing by (i) Venetoclax + Azacitidine or (ii) TestArticle plus Venetoclax + Azacitidine, across different cell types, as further described in Example8. FIG.16 is a graph showing percentage of cells remaining following exposure of the cells to Test Article, as further described in Example 9. FIG.17 is a graph showing percent cell depletion following exposure of the cells to Test Article, as further described in Example 10. DETAILED DESCRIPTION The present disclosure relates to methods of treating leukemia using a heterobifunctional molecule, referred to as a cytotoxicity targeting chimera (CyTaC) or antibody recruiting molecule (ARM), that is able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. The therapeutic methods, heterobifunctional molecules, anti-cotinine antibody or antigen-binding fragment thereof, and pharmaceutical compositions are described in more detail below. A. Therapeutic Methods One aspect of the disclosure provides a method of treating a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, to thereby treat the leukemia, wherein said compound of Formula I is described in Part B below. Another aspect of the disclosure provides a method of treating a leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, to thereby treat the leukemia, wherein said compound of Formula I is described in Part B below. Another aspect of the disclosure provides a method of depleting C-C motif chemokine receptor 2 (CCR2)-expressing cells in a patient suffering from a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein said compound of Formula I is described in Part B below. Another aspect of the disclosure provides a method of depleting C-C motif chemokine receptor 2 (CCR2)-expressing cells in a patient suffering from a leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein said compound of Formula I is described in Part B below. In certain embodiments, the CCR2-expressing cells are myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), neutrophils, macrophages, B regulatory cells (Bregs), CD8 regulatory cells, (CD8regs), exhausted T cells, or cancer-associated fibroblasts (CAFs). Administration Aspects In certain embodiments, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously. In certain embodiments, the compound and the antibody, or antigen-binding fragment thereof, are administered sequentially. Types of Leukemia In certain embodiments, the leukemia is chronic myelomonocytic leukemia. In certain embodiments, the chronic myelomonocytic leukemia is a dysplastic chronic myelomonocytic leukemia. In certain embodiments, the chronic myelomonocytic leukemia is a proliferative chronic myelomonocytic leukemia. In certain embodiments, the chronic myelomonocytic leukemia is of category CMML-0. In certain embodiments, the chronic myelomonocytic leukemia is of category CMML-1. In certain embodiments, the chronic myelomonocytic leukemia is of category CMML-2. The CMML-0, CMML-1, and CMML-2 classifications were established by the World Health Organization and are used by practitioners in the medical field. In certain embodiments, CMML-0 is characterized by patient blood containing about 2% blast cells and patient bone marrow containing about 5% blast cells. In certain embodiments, CMML- 1 is characterized by patient blood containing from about 2% to about 4% blast cells and patient bone marrow containing from about 5% to about 9% blast cells. In certain embodiments, CMML-2 is characterized by patient blood containing from about 5% to about 19% blast cells and patient bone marrow containing from about 10% to about 19% blast cells. In certain embodiments, a chronic myelomonocytic leukemia that is dysplastic is characterized by the patient’s white blood cell count being less than 13 x 109 / L of blood. In certain embodiments, a chronic myelomonocytic leukemia that is proliferative is characterized by the patient’s white blood cell count being at least 13 x 109 / L of blood. In certain embodiments, the leukemia is acute myeloid leukemia. In certain embodiments, the acute myeloid leukemia is an undifferentiated acute myeloblastic leukemia, an acute myeloblastic leukemia with minimal maturation, an acute myeloblastic leukemia with maturation, an acute promyelocytic leukemia, an acute myelomonocytic leukemia, an acute myelomonocytic leukemia with eosinophilia, an acute monocytic leukemia, or an acute erythroid leukemia. In certain embodiments, the acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 8 and 21 [t(8;21)], or (b) an acute myeloid leukemia with a translocation or inversion in chromosome 16 [t(16;16) or inv(16)]. In certain embodiments, the acute myeloid leukemia is (a) an acute myeloid leukemia with the PML-RARA fusion gene, or (b) an acute myeloid leukemia with a translocation between chromosomes 9 and 11 [t(9;11)]. In certain embodiments, acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 6 and 9 [t(6:9)], or (b) an acute myeloid leukemia with a translocation or inversion in chromosome 3 [t(3;3) or inv(3)]. In certain embodiments, the acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 1 and 22 [t(1:22)], or (b) an acute myeloid leukemia with a BCR-ABL1 (BCR- ABL) fusion gene. In certain embodiments, the acute myeloid leukemia is (a) an acute myeloid leukemia with mutated NPM1 gene, or (b) an acute myeloid leukemia a biallelic mutation of the CEBPA gene. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a mutated RUNX1 gene. In certain embodiments, the leukemia is a monocytic leukemia. In certain embodiments, the leukemia is an acute monocytic leukemia, acute myelomonocytic leukemia, or chronic myelomonocytic leukemia. In certain embodiments, the leukemia is a myelomonocytic / monocytic acute myeloid leukemia. In certain embodiments, the leukemia is a myelomonocytic acute myeloid leukemia. In certain embodiments, the leukemia is a monocytic acute myeloid leukemia. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a translocation between chromosomes 8 and 21 [t(8;21)]. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a translocation or inversion in chromosome 16 [t(16;16) or inv(16)]. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with the PML-RARA fusion gene. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a translocation between chromosomes 9 and 11 [t(9;11)]. In certain embodiments, acute myeloid leukemia is an acute myeloid leukemia with a translocation between chromosomes 6 and 9 [t(6:9)]. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a translocation or inversion in chromosome 3 [t(3;3) or inv(3)]. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a translocation between chromosomes 1 and 22 [t(1:22)]. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with a BCR-ABL1 (BCR-ABL) fusion gene. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia with mutated NPM1 gene. In certain embodiments, the acute myeloid leukemia is an acute myeloid leukemia a biallelic mutation of the CEBPA gene. In certain embodiments, the acute myeloid leukemia is one of those recited in the following table, based on classifications by the World Health Organization:

[0002] wherein “AML” refers to acute myeloid leukemia; “add” refers to addition of genetic material; “APL” refers to acute promyelocytic leukemia; “del” refers to deletion of genenetic material; “inv” refers to an inversion in a chromosome; “MDS” refers to myelodysplastic syndromes; “MPN” refers to myeloproliferative neoplasm; “p” refers to the short arm of a chromosome (the upper half); “q” refers to the long arm of a chromosome (the lower half); “t” refers to a translocation between chromosomes. In certain embodiments, the leukemia is juvenile myelomonocytic leukemia. In certain embodiments, the juvenile myelomonocytic leukemia is of Category 1. In certain embodiments, the juvenile myelomonocytic leukemia is of Category 2. In certain embodiments, the juvenile myelomonocytic leukemia is of Category 3. In certain embodiments, the patient suffering from juvenile myelomonocytic leukemia has a mutation in a gene of the RAS pathway. In certain embodiments, the patient suffering from juvenile myelomonocytic leukemia features a Monosomy 7 or chromosome 7 abnormality. Juvenile myelomonocytic leukemia of Category 1 is a juvenile myelomonocytic leukemia having all the following features: ^ Presence of an enlarged spleen ^ A persistent elevated monocyte count in the blood (greater than 1x109 / L which is equivalent to 1,000 monocytes per microliter of blood (1,000 / µl) ^ The absence of the Philadelphia chromosome (Ph chromosome) and the BCR-ABL1 gene rearrangement (the Ph chromosome is an abnormality of chromosome 22 found in the marrow and blood cells of patients with CML) ^ Less than 20 percent blast cells circulating in the blood and present in the bone marrow. Juvenile myelomonocytic leukemia of Category 2 is a juvenile myelomonocytic leukemia having at least one of the following features: ^ Somatic (change in DNA that happens after conception) mutation in PTPN11, KRAS or NRAS genes ^ Clinical diagnosis of neurofribromatosis type 1 (NF1) or NF1 gene mutation ^ Germline CBL gene mutation. Juvenile myelomonocytic leukemia of Category 3 is a juvenile myelomonocytic leukemia having at least two of the following features (and the patient does not meet juvenile myelomonocytic leukemia of category 2): ^ Monosomy 7 (only one chromosome from a pair) or any other chromosomal abnormality ^ Higher levels of hemoglobin F than is normal for the age of the patient ^ Myeloid precursors (predecessor of red blood cells, platelets and some types of white blood cells) in the blood ^ Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity in colony assay ^ Hyperphosphorylation of STAT5. In certain embodiments, the patient has an elevated level of monocyte cells. In certain embodiments, the leukemia is characterized by the feature that at least 20% of the pathologic leukemia cells in a sample from the patient are monocytic cells. In certain embodiments, the leukemia is characterized by the feature that at least 40% of the pathologic leukemia cells in a sample from the patient are monocytic cells. In certain embodiments, the leukemia is characterized by the feature that from about 20% to about 40% of the pathologic leukemia cells in a sample from the patient are monocytic cells. In certain embodiments, the patient has an elevated level of expression of CCR2 in leukemia cells. In certain embodiments, the patient has an elevated level of expression of CCR2 in leukemia cells in the range of moderate to high level of expression of CCR2 in leukemia cells. In certain embodiments, the patient has an elevated level of expression of CCR2 in leukemia cells that is a high level of expression of CCR2 in leukemia cells. In certain embodiments, the leukemia is characterized by the feature that at least 20% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 30% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 40% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 50% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 60% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 70% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 80% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that at least 90% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 20% to about 90% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 40% to about 90% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 50% to about 99% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 70% to about 90% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 70% to about 99% of the pathologic cells are CCR2 positive. In certain embodiments, the leukemia is characterized by the feature that from about 80% to about 99% of the pathologic cells are CCR2 positive. In certain embodiments, the patient has an elevated level of expression of CD14 in leukemia cells. In certain embodiments, the patient has an elevated level of expression of CD14 in leukemia cells in the range of moderate to high level of expression of CD14 in leukemia cells. In certain embodiments, the patient has an elevated level of expression of CD14 in leukemia cells that is a high level of expression of CD14 in leukemia cells. In certain embodiments, the leukemia is characterized by the feature that at least 10% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 20% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 30% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 40% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 50% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 60% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 70% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 80% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that at least 90% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 20% to about 90% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 40% to about 90% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 50% to about 99% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 70% to about 90% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 70% to about 99% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is characterized by the feature that from about 80% to about 99% of the pathologic cells are CD14 positive. In certain embodiments, the leukemia is a drug-resistant leukemia. For example, in certain embodiments, the patient suffering from leukemia has been administered at least one prior anti-cancer agent to treat the leukemia, but the leukemia was refractory to the at least one prior anti-cancer agent. In certain embodiments, the patient suffering from leukemia has been administered at least two prior anti-cancer agents to treat the leukemia, but the leukemia was refractory to the at least two prior anti-cancer agents. In certain embodiments, the patient suffering from leukemia has been administered at least one prior anti-cancer agent to treat the leukemia. In certain embodiments, the patient suffering from leukemia has been administered at least two prior anti-cancer agents to treat the leukemia. In certain embodiments, the leukemia is a drug-resistant acute myeloid leukemia. In certain embodiments, the leukemia is a chemotherapy-resistant leukemia (e.g., a doxorubicin- resistant leukemia). In certain embodiments, the leukemia is a BCL-2 resistant acute myeloid leukemia (e.g., a venetoclax-resistant acute myeloid leukemia). In certain embodiments, the leukemia is resistant to a tyrosine kinase inhibitor. In certain embodiments, the leukemia is an acute myeloid leukemia that is resistant to a tyrosine kinase inhibitor (e.g., an imatinib-resistant acute myeloid leukemia). In certain embodiments, the leukemia is resistant to a FLT3 inhibitor. In certain embodiments, the leukemia is an acute myeloid leukemia that is resistant to a FLT3 inhibitor (e.g., a quizartinib-resistant acute myeloid leukemia ). In certain embodiments, the leukemia is resistant to cytarabine. In certain embodiments, the leukemia is an acute myeloid leukemia that is resistant to cytarabine. Additionally Exemplary Features In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously from a single composition, including as a fixed-dose composition or by pre-mixing the compound and the antibody, or antigen-binding fragment thereof, prior to administration. For example, the compound and the antibody, or antigen-binding fragment thereof, can be pre-mixed about 2 seconds to about 30 seconds, about 30 seconds to about 2 minutes, about 2 minutes to about 10 minutes, about 10 minutes to about 30 minutes, or about 30 minutes to about 2 hours prior to administration. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously from two separate compositions. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered sequentially. In certain embodiments, the compound and the antibody, or antigen-binding fragment thereof, whether administered simultaneously or sequentially, may be administered by the same route or may be administered by different routes. In one embodiment, the compound and the antibody, or antigen-binding fragment thereof, are both administered intraveneously or subcutaneously, in the same composition or in separate compositions. In another embodiment, the compound is administered orally and the antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered in a molar ratio of compound to antibody, or antigen-binding fragment thereof, of about 2:1, about 1.8:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.8, about 1:2, about 2:1 to about 1.5:1, about 1.5:1 to about 1.2:1, about 1.2:1 to about 1:1, about 1:1 to about 1:1.2, about 1:1.2 to about 1:1.5, or about 1:1.5 to about 1:2. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are present as a combination in a molar ratio of compound to antibody, or antigen-binding fragment thereof, of about 2:1, about 1.8:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.8, about 1:2, about 2:1 to about 1.5:1, about 1.5:1 to about 1.2:1, about 1.2:1 to about 1:1, about 1:1 to about 1:1.2, about 1:1.2 to about 1:1.5, or about 1:1.5 to about 1:2. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered at a dosage of compound of 0.0001 mg / kg to 1 mg / kg and antibody of 0.01 mg / kg to 100 mg / kg. For example, in a further embodiment, the compound is administered at a dosage of about 0.0001 mg / kg to about 0.0002 mg / kg, about 0.0002 mg / kg to about 0.0003 mg / kg, about 0.0003 mg / kg to about 0.0004 mg / kg, about 0.0004 mg / kg to about 0.0005 mg / kg, about 0.0005 mg / kg to about 0.001 mg / kg, about 0.001 mg / kg to about 0.002 mg / kg, about 0.002 mg / kg to about 0.003 mg / kg, about 0.003 mg / kg to about 0.004 mg / kg, about 0.004 mg / kg to about 0.005 mg / kg, about 0.005 mg / kg to about 0.01 mg / kg, about 0.01 mg / kg to about 0.02 mg / kg, about 0.02 mg / kg to about 0.03 mg / kg, about 0.03 mg / kg to about 0.04 mg / kg, about 0.04 mg / kg to about 0.05 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.2 mg / kg, about 0.2 mg / kg to about 0.3 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.4 mg / kg to about 0.5 mg / kg, and / or about 0.5 mg / kg to about 1 mg / kg, and the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 0.01 mg / kg to about 0.02 mg / kg, about 0.02 mg / kg to about 0.03 mg / kg, about 0.03 mg / kg to about 0.04 mg / kg, about 0.04 mg / kg to about 0.05 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.2 mg / kg, about 0.2 mg / kg to about 0.3 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.4 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 1 mg / kg to about 2 mg / kg, about 2 mg / kg to about 3 mg / kg, about 3 mg / kg to about 4 mg / kg, about 4 mg / kg to about 5 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 20 mg / kg, about 20 mg / kg to about 25 mg / kg, about 25 mg / kg to about 30 mg / kg, about 30 mg / kg to about 35 mg / kg, about 35 mg / kg to about 40 mg / kg, about 40 mg / kg to about 45 mg / kg, about 45 mg / kg to about 50 mg / kg, about 50 mg / kg to about 60 mg / kg, about 60 mg / kg to about 70 mg / kg, about 70 mg / kg to about 80 mg / kg, about 80 mg / kg to about 90 mg / kg, and / or about 90 mg / kg to about 100 mg / kg. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered at a dosage of compound of 0.007 mg to 70 mg and antibody of 0.7 mg to 7000 mg. For example, in a further embodiment, the compound is administered at a dosage of about 0.007 mg to about 0.01 mg, about 0.01 mg to about 0.02 mg, about 0.02 mg to about 0.03 mg, about 0.03 mg to about 0.04 mg, about 0.04 mg to about 0.05 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, and / or about 60 mg to about 70 mg, and the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 0.7 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 500 mg, about 500 mg to about 1000 mg, about 1000 mg to about 1500 mg, about 1500 mg to about 2000 mg, about 2000 mg to about 2500 mg, about 2500 mg to about 3000 mg, about 3000 mg to about 3500 mg, about 3500 mg to about 4000 mg, about 4000 mg to about 4500 mg, about 4500 mg to about 5000 mg, about 5000 mg to about 5500 mg, about 5500 mg to about 6000 mg, about 6000 mg to about 6500 mg, and / or about 6500 mg to about 7000 mg. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered in a molar ratio and / or dosage as described herein once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks for a period of one week to one year, such as a period of one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months. In a further embodiment, the present disclosure provides a therapeutically effective amount of the compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof for use in therapy. The compound of Formula I and anti-cotinine antibody, or antigen- binding fragment thereof can be used in treating or preventing a disease or disorder described herein. In a further embodiment, the present disclosure provides a therapeutically effective amount of the compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof for the manufacture of a medicament. The medicament can be used in treating or preventing a disease or disorder described herein. B. Compound of Formula I In one aspect, the present disclosure provides a compound of Formula I, which is represented by pharmaceutically acceptable salt thereof, wherein: R1is C1-4alkyl or C3-6cycloalkyl; R2is hydrogen or C1-4alkyl; R3is hydrogen or C1-4alkyl; and L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g), (L-h), (L-i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv). In one embodiment of the disclosure L is a divalent linker of Formula (L-a): stereoisomer thereof, wherein: Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, Ring A and Ring B of Formula (L-a) are each independently . In another embodiment, L is a divalent linker of Formula (L-a-i): stereoisomer thereof, wherein: Ring A is C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, Ring A of Formula (L-a-i) is , , , In another embodiment, L is a divalent linker of Formula (L-a-ii): -ii), or a stereoisomer thereof, wherein: L1ais C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; L2ais -O-, -NHC(O)-, or -CH2-O-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from wherein: j is 1, 2, 3, or 4; k is 0, 1, 2, or 3; the sum of j and k is 2, 3, or 4; q is 1 or 2; r is 1 or 2; s is 0 or 1; the sum of q, r, and s is 2 or 3; X1and X2are independently -O- or NRa; and each Rais independently hydrogen or C1-3 alkyl; wherein represents a covalent bond to the C(O) group of Formula (L-a), (L-a-i), or (L-a-ii), and represents a covalent bond to Ring B of Formula (L-a) or to the cyclohexylene group of Formula (L-a-i) or (L-a-ii). In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2O- , -(CH2)3O-, -(CH2)4O-, -(CH2)2OCH2-, -(CH2)3OCH2-, -(CH2)2O(CH2)2-, -CH2OCH2-, -CH2O(CH2)2- , -CH2O(CH2)3-, -CH2OCH2O-, or -CH2OCH2OCH2-. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2O-, -(CH2)3O-, -(CH2)2OCH2-, or -(CH2)3OCH2-. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NRa-, -(CH2)3NRa-, - (CH2)4NRa-, -(CH2)2NRaCH2-, -(CH2)3NRaCH2-, -(CH2)2NRa(CH2)2-, -CH2NRaCH2-, - CH2NRa(CH2)2-, -CH2NRa(CH2)3-, -CH2NRaCH2NRa-, or -CH2NRaCH2NRaCH2-, wherein each Rais independently hydrogen or C1-3alkyl. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NRa-, -(CH2)3NRa-, -(CH2)2NRaCH2-, or -(CH2)3NRaCH2-, wherein Rais hydrogen or C1-3alkyl. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NH-, -(CH2)3NH-, -(CH2)4NH-, -(CH2)2NHCH2-, -(CH2)3NHCH2-, - (CH2)2NH(CH2)2-, -CH2NHCH2-, -CH2NH(CH2)2-, -CH2NH(CH2)3-, -CH2NHCH2NH-, or - CH2NHCH2NHCH2-. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NH-, -(CH2)3NH-, -(CH2)2NHCH2-, or -(CH2)3NHCH2-. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH2OCH2NRa-, -CH2NRaCH2O-, - CH2OCH2NRaCH2-, -CH2NRaCH2OCH2-, wherein Rais independently hydrogen or C1-3alkyl. In another embodiment, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH2OCH2NH-, - CH2NHCH2O-, -CH2OCH2NHCH2-, -CH2NHCH2OCH2-. In another embodiment, L is a divalent linker of Formula (L-a-iii): -iii), or a stereoisomer thereof, wherein: p is 1 or 2; m is 1 or 2; and n is 1, 2, or 3; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-a) selected from the group consisting of: , , ,

[0003] In another embodiment, L is a divalent linker represented by: In another embodiment, L is a divalent linker of Formula (L-b): stereoisomer thereof, wherein: Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, - C(O)NR1b-, or -NR1bC(O)-; or L ; and each R1bis independently hydrogen or C1-3 alkyl; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). , In another embodiment, L is a divalent linker of Formula (L-b-i): stereoisomer thereof, wherein: L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, - C(O)NR1b-, or -NR1bC(O)-; or L2bis wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; each R1bis independently hydrogen or C1-3alkyl; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L2bof Formula (L-b) or (L-b-i) is selected from r wherein: j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the sum of j and k is 5, 6, 7, 8, 9, 10, or 11; q is 1, 2, 3, 4, 5, 6, 7, 8, or 9; r is 1, 2, 3, 4, 5, 6, 7, 8, or 9; s is 0, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of q, r, and s is 4, 5, 6, 7, 8, 9, or 10; t is 1, 2, 3, 4, 5, 6, or 7; u is 1, 2, 3, 4, 5, 6, or 7; v is 1, 2, 3, 4, 5, 6, or 7; w is 0, 1, 2, 3, 4, 5, or 6; the sum of t, u, v, and w is 3, 4, 5, 6, 7, 8, or 9; a is 1, 2, 3, 4, or 5; b is 1, 2, 3, 4, or 5; c is 1, 2, 3, 4, or 5; d is 1, 2, 3, 4, or 5; e is 0, 1, 2, 3, or 4; the sum of a, b, c, d, and e is 4, 5, 6, 7, or 8; X1, X2, X3, and X4are independently -O-, -NR1b-, -C(O)NR1b-, or -NR1bC(O)-; and each R1bis independently hydrogen or C1-3alkyl; wherein represents a covalent bond to L1bof Formula (L-b) or (L-b-i), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-b) selected from the group consisting of: , , , , , , , , , , , , , , , , d In another embodiment, L is a divalent linker of Formula (L-c): (L-c), or a stereoisomer thereof, wherein: L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the NH group of Formula (I), and s a covalent bond to the methylene group of Formula (I). , In another embodiment, L is a divalent linker of Formula (L-c-i): (L-c-i), or a stereoisomer thereof, wherein: L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L1cof Formula (L-c) or (L-c-i) is selected from wherein: j is 1, 2, 3, 4, 5, 6, 7, 8, or 9; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of j and k is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 1, 2, 3, 4, 5, 6, or 7; r is 1, 2, 3, 4, 5, 6, or 7; s is 0, 1, 2, 3, 4, 5, or 6; the sum of q, r, and s is 2, 3, 4, 5, 6, 7, or 8; t is 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, or 5; v is 1, 2, 3, 4, or 5; w is 0, 1, 2, 3, or 4; the sum of t, u, v, and w is 3, 4, 5, 6, or 7; and X1, X2and X3are independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the C(O) group of Formula (L-c) or (L-c-i), and represents a covalent bond to the ring of Formula (L-c) or (L-c-i). In another embodiment, L2cof Formula (L-c) or (L-c-i) is selected from wherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; the sum of j and k is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 2, 3, 4, 5, 6, or 7; r is 1, 2, 3, 4, 5, 6, 7, or 8; s is 0, 1, 2, 3, 4, 5, 6, or 7; the sum of q, r, and s is 1, 2, 3, 4, 5, 6, 7, or 8; t is 0, 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, 5, or 6; v is 1, 2, 3, 4, 5, or 6; w is 0, 1, 2, 3, 4, or 5; the sum of t, u, v, and w is 2, 3, 4, 5, 6, or 7; and X1, X2and X3are independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the ring of Formula (L-c) or (L-c-i), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-c) selected from the group consisting of: , , , , , , , In another embodiment, L is a divalent linker of Formula (L-d): wherein: L1dis C12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, - C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; wherein represents a covalent bond to the NH group of Formula (I), and s a covalent bond to the methylene group of Formula (I). In another embodiment, L1dof Formula (L-d) is selected from , wherein: j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; the sum of j and k is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; the sum of q, r, and s is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; t is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; u is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; the sum of t, u, v, and w is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; e is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; the sum of a, b, c, d, and e is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; h is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; the sum of f, g, h, i, y, and z is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; and X1, X2, X3, X4, and X5are independently -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; wherein represents a covalent bond to the C(O) group of Formula (L-d), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-d) selected from the group consisting of: , , , , , , , , , , , , , , , In another embodiment, L is a divalent linker of Formula (L-e): wherein: n is an integer of 3 to 50; wherein represents a covalent bond to the NH group of Formula (I), an represents a covalent bond to the methylene group of Formula (I). In another embodiment, n of Formula (L-e) is 3 to 25, 3 to 10, 3 to 8, 3 to 7, 3 to 5, or 3 to 4. In another embodiment, n of Formula (L-e) is 3, 4, 5, 7, 8, 22, or 50. In another embodiment, L is a divalent linker of Formula (L-f): (L-f), or a stereoisomer thereof, wherein: L1fis a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L1fof Formula (L-f) is selected from wherein: j is 1, 2, 3, 4, or 5; k is 0, 1, 2, 3, or 4; the sum of j and k is 1, 2, 3, 4, or 5; q is 1, 2, or 3; r is 1, 2, or 3; s is 0, 1, 2; the sum of q, r, and s is 2, 3, or 4; and X1and X2are independently -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)-NHC(O)-; wherein represents a covalent bond to the C(O) group of Formula (L-f), and represents a covalent bond to the ring of Formula (L-f). In another embodiment, L2fof Formula (L-f) is selected from wherein: j is 1, 2, 3, 4, or 5; k is 0, 1, 2, 3, or 4; the sum of j and k is 1, 2, 3, 4, or 5; q is 1, 2, or 3; r is 1, 2, or 3; s is 0, 1, 2; and the sum of q, r, and s is 2, 3, or 4; wherein epresents a covalent bond to the ring of Formula (L-f), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-f) selected from the group consisting of: : wherein: Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2gis wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L1g; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-g-i): wherein: L1gis a bond, -CH2-, -NH-, or -O-; L2gis wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L1g; Z1, Z2, and Z3are each independently selected from N or CH, provided that one or two of Z1, Z2, and Z3is N; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-g) selected from the group consisting of: , , , , In another embodiment, L is a divalent linker of Formula (L-h): stereoisomer thereof, wherein: each Z1is independently N or CH; L1his a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-; L2his C2-10linear alkylene or , wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1hand represents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or -C(O)CH2-; and m is 1, 2, or 3; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-h) selected from the group consisting of: , , , , , , , O , In another embodiment, L is a divalent linker of Formula (L-i): wherein: L1iis a bond, C1-12linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L3iand represents a covalent bond to NH; L2iis a bond, C1-12linear alkylene, or , wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN; and L3iis a bond or -C(O)-; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-i) selected from the group consisting of: , , a In another embodiment, L is a divalent linker of Formula (L-j): stereoisomer thereof, wherein: Z1is C, CH, or N; each of Z2, Z3, Z4and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L1j; and epresents a single bond or a double bond; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-j) selected from the group consisting of: , In another embodiment, L is a divalent linker of Formula (L-k): stereoisomer thereof, wherein: Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH- or -NHC(O)-; and L2kis a C3-8straight chain alkylene or , wherein n is 1, 2, or 3, and represents a covalent bond to L1k; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-k) selected from the group consisting of: . In another embodiment, L is a divalent linker of Formula (L-m): stereoisomer thereof, wherein: Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atoms are replaced with F; L1mis a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH- or -NHS(O)2-; and L2mis C3-6linear alkylene, C3-6cycloalkylene, or , wherein n is 1 or 2, and represents a covalent bond to L1m; wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-m) selected from the group consisting of: , , , , d In another embodiment, L is a divalent linker of Formula (L-n-i): wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-n-ii): wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-n-iii): wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, L is a divalent linker of Formula (L-n-iv): wherein represents a covalent bond to the NH group of Formula (I), and represents a covalent bond to the methylene group of Formula (I). In another embodiment, R1is methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, or t-butyl. In another embodiment, R1is methyl. In another embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the compound of Formula (I) is selected from a compound as listed in Table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of Formula (I) is selected from a compound as listed in Table 1. Table 1.

[0004] O O O O N N

[0005] Compounds in Table 1 may be prepared according to procedures described in international patent application publication WO 2023 / 017483, which is hereby incorporated by reference. Experimental results demonstrating the performance benefits of exemplary compounds is described in the Examples. Experimental results for additional compounds from Table 1 may be generated by substituting the CyTAC used in the Example with such other CyTAC compound from Table 1. CCR2 Target and CCR2-Binding Moieties The compounds of Formula (I) as disclosed herein are heterobifunctional synthetic agents designed such that one terminus interacts with a cell surface CCR2 target, while the other terminus binds a specific antibody. More specifically, the ARM simultaneously binds the cell surface CCR2 target as well as the specific antibody. This ternary complex directs immune surveillance to CCR2-expressing tissue / cells and unites the mechanisms of antibody function with the dose-control of small molecules. This mechanism may include antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), or complement dependant cytotocity (CDC), and preferably includes ADCC. The same Fc receptor expressing immune cells that initiate destruction of the ARM / antibody tagged cells also participate in presentation of endogenous antigens for the potential for long term cellular immunity. The compounds of Formula (I) as disclosed herein include a CCR2-binding moiety that is capable of binding CCR2 present on the surface of a cell. In one embodiment, the CCR2 is expressed on a leukemia cell, such as one of the leukemia types set forth herein. C. Anti-Cotinine Antibodies The present disclosure provides an antibody, or antigen-binding fragment thereof, that binds to a cotinine moiety. As used herein, the term “anti-cotinine antibody or antigen-binding fragment thereof” refers to an antibody, or antigen binding fragment thereof that binds to a cotinine moiety. Cotinine has the following structure: . As used herein, the term “cotinine moiety” refers to cotinine or an analog of cotinine. Compounds of Formula (I) described herein comprise a cotinine moiety linked via a linker to a CCR2-binding moiety. In one embodiment, the cotinine moiety has the following structure: wherein R1is C1-4alkyl or C3-6cycloalkyl. In another embodiment, R1is methyl, ethyl, 1-propyl, 2- propyl, 1-butyl, 2-butyl, or t-butyl. In another embodiment, R1is methyl. In another embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, 23(9): 1126-1136). The term, full, whole or intact antibody, used interchangeably herein, refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons. An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment. The Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light). The Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway. The five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called µ, α, γ, ε and δ respectively, each heavy chain can pair with either a Κ or λ light chain. The majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgG1, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region. “CDRs” are defined as the complementarity determining region amino acid sequences of an antibody or antigen binding fragment thereof. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs. Throughout this specification, amino acid residues in variable domain sequences and variable domain regions within full-length antigen binding sequences, e.g., within an antibody heavy chain sequence or antibody light chain sequence, are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention. For further information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987). It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out in Chothia et al., Nature, 1989, 342: 877-883. The structure and protein folding of the antigen binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person. Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. Table 2 below represents one definition using each numbering convention for each CDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used. Table 2 In a further embodiment, the anti-cotinine antibody is humanized. In a further embodiment, the Fc region of the anti-cotinine antibody is modified to increase ADCC activity, ADCP activity, and / or CDC activity, suitable modifications of which are provided below. In a further embodiment, the Fc region of the anti-cotinine antibody is modified to increase ADCC activity. Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to C1q or Fcγ receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (neonatal Fc receptor). The term “effector function” as used herein refers to one or more of antibody-mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated complement activation including complement-dependent cytotoxicity (CDC), complement- dependent cell-mediated phagocytosis (CDCP), antibody dependent complement-mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP). The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), FcRn, C1q, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function. Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcγRIII, or monocytes / macrophages via FcγRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via C1q. For example, an antibody, or antigen binding fragment thereof, of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay. Examples of such assays can be found in Shields et al., The Journal of Biological Chemistry, 2001, 276: 6591-6604; Chappel et al., The Journal of Biological Chemistry, 1993, 268: 25124-25131; Lazar et al., PNAS, 2006, 103: 4005-4010. Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38. The effects of mutations on effector functions (e.g., FcRn binding, FcγRs and C1q binding, CDC, ADCML, ADCC, ADCP) can be assessed, e.g., as described in Grevys et al., J Immunol., 2015,194(11): 5497–5508; Tam et al., Antibodies, 2017, 6(3): 12; or Monnet et al., mAbs, 2014, 6(2): 422-436. Throughout this specification, amino acid residues in Fc regions, in antibody sequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention. Human IgG1 constant regions containing specific mutations have been shown to enhance binding to Fc receptors. In some cases these mutations have also been shown to enhance effector functions, such as ADCC and CDC, as described below. Antibodies, or antigen binding fragments thereof, of the present invention may include any of the following mutations. Enhanced CDC: Fc engineering can be used to enhance complement-based effector function. For example (with reference to IgG1), K326W / E333S; S267E / H268F / S324T; and IgG1 / IgG3 cross subclass can increase C1q binding; E345R (Diebolder et al., Science, 2014, 343: 1260-1293) and E345R / E430G / S440Y results in preformed IgG hexamers (Wang et al., Protein Cell, 2018, 9(1): 63–73). Enhanced ADCC: Fc engineering can be used to enhance ADCC. For example (with reference to IgG1), F243L / R292P / Y300L / V305I / P396L; S239D / I332E; and S298A / E333A / K334A increase FcγRIIIa binding; S239D / I332E / A330L increases FcγRIIIa binding and decreases FcγRIIb binding; G236A / S239D / I332E improves binding to FcγRIIa, improves the FcγRIIa / FcγRIIb binding ratio (activating / inhibitory ratio), and enhances phagocytosis of antibody- coated target cells by macrophages. An asymmetric Fc in which one heavy chain contains L234Y / L235Q / G236W / S239M / H268D / D270E / S298A mutations and D270E / K326D / A330M / K334E in the opposing heavy chain, increases affinity for FcγRIIIa F158 (a lower-affinity allele) and FcγRIIIa V158 (a higher-affinity allele) with no increased binding affinity to inhibitory FcγRIIb (Mimoto et al., mAbs, 2013, 5(2): 229-236). Enhanced ADCP: Fc engineering can be used to enhance ADCP. For example (with reference to IgG1), G236A / S239D / I332E increases FcγRIIa binding and increases FcγRIIIa binding (Richards, J. et al., Mol. Cancer Ther., 2008, 7: 2517-2527). Increased co-engagement: Fc engineering can be used to increase co-engagement with FcRs. For example (with reference to IgG1), S267E / L328F increases FcγRIIb binding; N325S / L328F increases FcγRIIa binding and decreases FcγRIIIa binding Wang et al., Protein Cell, 2018, 9(1): 63–73). In a further embodiment, an antibody, or antigen binding fragment thereof, of the present invention may comprise a heavy chain constant region with an altered glycosylation profile, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, e.g., enhanced ADCC, enhanced CDC, or both enhanced ADCC and CDC. Examples of suitable methodologies to produce an antibody, or antigen binding fragment thereof, with an altered glycosylation profile are described in WO 2003 / 011878, WO 2006 / 014679 and EP1229125. The absence of the α1,6 innermost fucose residues on the Fc glycan moiety on N297 of IgG1 antibodies enhances affinity for FcγRIIIA. As such, afucosylated or low fucosylated monoclonal antibodies may have increased therapeutic efficacy (Shields et al., J Biol Chem., 2002, 277(30): 26733-40 and Monnet et al., mAbs, 2014, 6(2): 422-436). In one embodiment there is provided an antibody, or antigen binding fragment thereof, comprising a chimeric heavy chain constant region. In an embodiment, the antibody, or antigen binding fragment thereof, comprises an IgG1 / IgG3 chimeric heavy chain constant region, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, for example enhanced ADCC or enhanced CDC, or enhanced ADCC and CDC functions. For example, a chimeric antibody, or antigen binding fragment thereof, of the invention may comprise at least one CH2 domain from IgG3. In one such embodiment, the antibody, or antigen binding fragment thereof, comprises one CH2 domain from IgG3 or both CH2 domains may be from IgG3. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain, an IgG3 CH2 domain, and an IgG3 CH3 domain. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain, an IgG3 CH2domain, and an IgG3 CH3 domain except for position 435 that is histidine. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain and at least one CH2 domain from IgG3. In an embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain and the following residues, which correspond to IgG3 residues, in a CH2domain: 274Q, 276K, 296F, 300F and 339T. In an embodiment, the chimeric antibody, or antigen binding fragment thereof, also comprises 356E, which corresponds to an IgG3 residue, within a CH3 domain. In an embodiment, the antibody, or antigen binding fragment thereof, also comprises one or more of the following residues, which correspond to IgG3 residues within a CH3 domain: 358M, 384S, 392N, 397M, 422I, 435R, and 436F. Also provided is a method of producing an antibody, or antigen binding fragment thereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleic acid sequence encoding a chimeric Fc region having both IgG1 and IgG3 Fc region amino acid residues (e.g., as described above); and b) recovering the antibody, or antigen binding fragment thereof. Such methods for the production of antibody, or antigen binding fragment thereof, with chimeric heavy chain constant regions can be performed, for example, using the COMPLEGENT technology system available from BioWa, Inc. (Princeton, NJ) and Kyowa Hakko Kirin Co., Ltd. The COMPLEGENT system comprises a recombinant host cell comprising an expression vector in which a nucleic acid sequence encoding a chimeric Fc region having both IgG1 and IgG3 Fc region amino acid residues is expressed to produce an antibody, or antigen binding fragment thereof, having enhanced CDC activity, i.e., CDC activity is increased relative to an otherwise identical antibody, or antigen binding fragment thereof, lacking such a chimeric Fc region, as described in WO 2007 / 011041 and US 2007 / 0148165, each of which are incorporated herein by reference. In an alternative embodiment, CDC activity may be increased by introducing sequence specific mutations into the Fc region of an IgG chain. Those of ordinary skill in the art will also recognize other appropriate systems. The present invention also provides a method of producing an antibody, or antigen binding fragment thereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleic acid encoding the antibody, or antigen binding fragment thereof, optionally wherein the FUT8 gene encoding alpha-1,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof. Such methods for the production of an antibody, or antigen binding fragment thereof, can be performed, for example, using the POTELLIGENT technology system available from BioWa, Inc. (Princeton, NJ) in which CHOK1SV cells lacking a functional copy of the FUT8 gene produce monoclonal antibodies having enhanced ADCC activity that is increased relative to an identical monoclonal antibody produced in a cell with a functional FUT8 gene as described in US Patent No. 7,214,775, US Patent No. 6,946,292, WO 00 / 61739 and WO 02 / 31240, all of which are incorporated herein by reference. Those of ordinary skill in the art will also recognize other appropriate systems. In one embodiment, the antibody, or antigen binding fragment thereof, is produced in a host cell in which the FUT8 gene has been inactivated. In a further embodiment, the antibody, or antigen binding fragment thereof, is produced in a - / - FUT8 host cell. In a further embodiment, the antibody, or antigen binding fragment thereof, is afucosylated at Asn297 (IgG1). It will be apparent to those skilled in the art that such modifications may not only be used alone but may be used in combination with each other in order to further enhance effector function. In one such embodiment, there is provided an antibody, or antigen binding fragment thereof, comprising a heavy chain constant region that comprises a both a mutated and chimeric heavy chain constant region, individually described above. For example, an antibody, or antigen binding fragment thereof, comprising at least one CH2domain from IgG3 and one CH2domain from IgG1, and wherein the IgG1 CH2 domain has one or more mutations at positions selected from 239, 332 and 330 (for example the mutations may be selected from S239D, I332E and A330L), such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g., enhanced ADCC or enhanced CDC, or enhanced ADCC and enhanced CDC in comparison to an equivalent antibody, or antigen binding fragment thereof, with an IgG1 heavy chain constant region lacking said mutations. In one embodiment, the IgG1 CH2 domain has the mutations S239D and I332E. In another embodiment, the IgG1 CH2 domain has the mutations S239D, A330L, and I332E. In an alternative embodiment, there is provided an antibody, or antigen binding fragment thereof, comprising both a chimeric heavy chain constant region and an altered glycosylation profile, as individually described above. In an embodiment, the antibody, or antigen binding fragment thereof, comprises an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less. In one such embodiment, the heavy chain constant region comprises at least one CH2domain from IgG3 and one CH2 domain from IgG1 and has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, for example wherein the antibody, or antigen binding fragment thereof, is defucosylated. Said antibody, or antigen binding fragment thereof, has an enhanced effector function, e.g., enhanced ADCC or enhanced CDC, or enhanced ADCC and enhanced CDC, in comparison to an equivalent antibody, or antigen binding fragment thereof, with an IgG1 heavy chain constant region lacking said glycosylation profile. In an alternative embodiment, the antibody, or antigen binding fragment thereof, has at least one IgG3 heavy chain CH2 domain and at least one heavy chain constant domain from IgG1 wherein both IgG CH2 domains are mutated in accordance with the limitations described herein. In one aspect, there is provided a method of producing an antibody, or antigen binding fragment thereof, according to the invention described herein comprising the steps of: a) culturing a recombinant host cell containing an expression vector comprising a nucleic acid sequence encoding a chimeric Fc domain having both IgG1 and IgG3 Fc domain amino acid residues (e.g., as described above); and wherein the FUT8 gene encoding alpha-1,6- fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof. Such methods for the production of an antibody, or antigen binding fragment thereof, can be performed, for example, using the ACCRETAMAB technology system available from BioWa, Inc. (Princeton, NJ) that combines the POTELLIGENT and COMPLEGENT technology systems to produce an antibody, or antigen binding fragment thereof, having both enhanced ADCC and CDC activity relative to an otherwise identical monoclonal antibody that lacks a chimeric Fc domain and that is fucosylated. In another embodiment, there is provided an antibody, or antigen binding fragment thereof, comprising a mutated and chimeric heavy chain constant region wherein said antibody, or antigen binding fragment thereof, has an altered glycosylation profile such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g., enhanced ADCC or enhanced CDC, or both enhanced ADCC and CDC. In one embodiment the mutations are selected from positions 239, 332 and 330, e.g., S239D, I332E and A330L. In a further embodiment the heavy chain constant region comprises at least one CH2 domain from IgG3 and one CH1 domain from IgG1. In one embodiment the heavy chain constant region has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, e.g., the antibody, or antigen binding fragment thereof, is defucosylated, such that said antibody, or antigen binding fragment thereof, has an enhanced effector function in comparison with an equivalent non- chimeric antibody, or antigen binding fragment thereof, lacking said mutations and lacking said altered glycosylation profile. In a further embodiment, the anti-cotinine antibody, or antigen binding fragment thereof, comprises a heavy chain CDR1 having SEQ ID NO: 1, a heavy chain CDR2 having SEQ ID NO: 2, a heavy chain CDR3 having SEQ ID NO: 3, a light chain CDR1 having SEQ ID NO: 4, a light chain CDR2 having SEQ ID NO: 5, and a light chain CDR3 having SEQ ID NO: 6. In a further embodiment, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E or S239D / I332E / A330L, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (VH) having SEQ ID NO: 7, a light chain variable region (VL) having SEQ ID NO: 8. In a further embodiment, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E or S239D / I332E / A330L, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. The present disclosure also provides a pharmaceutical composition comprising an anti- cotinine antibody, or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent. The present disclosure also provides a combination comprising the compound of Formula (I) as disclosed herein, and an anti-cotinine antibody, or antigen-binding fragment thereof as disclosed herein. The compound of Formula (I) and anti-cotinine antibody, or antigen binding fragment thereof can be present in the same composition or in separate compositions. In one embodiment, a combination comprises a pharmaceutical composition comprising the compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, a combination comprises a first pharmaceutical composition comprising a compound of Formula (I) as disclosed herein and a pharmaceutically acceptable carrier, diluent, or excipient; and a second pharmaceutical composition comprising an anti-cotinine antibody or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable carrier, excipient, or diluent. D. Combination Therapies The compounds of the invention may be employed alone or in combination with other therapeutic agents. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula (I) and the use of at least one other pharmaceutically active agent. The compounds of the invention and the other pharmaceutically active agents may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compounds of the invention and the other pharmaceutically active agents and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. It will be appreciated that when the compound of the present invention is administered in combination with one or more other therapeutically active agents normally administered by the inhaled, intravenous, oral, intranasal, ocular topical or other route, that the resultant pharmaceutical composition may be administered by the same route. Alternatively, the individual components of the composition may be administered by different routes. In one embodiment, the compounds and pharmaceutical composition disclosed herein are used in combination with, or include, one or more additional therapeutic agents. In a further embodiment, the additional therapeutic agent is a checkpoint inhibitor or an immune modulator. In a further embodiment, the checkpoint inhibitor is selected from a PD-1 inhibitor (e.g., an anti-PD-1 antibody including, but not limited to, pembrolizumab, nivolumab, cemiplimab, or dostarlimab), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody including, but not limited to, atezolizumab, avelumab, or durvalumab), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody including, but not limited to, ipilimumab or tremilumumab). In a further embodiment, the checkpoint inhibitor is selected from a CD226 axis inhibitor, including but not limited to a TIGIT inhibitor (e.g., an anti-TIGIT antibody), a CD96 inhibitor (e.g., an anti-CD96 antibody), and / or a PVRIG inhibitor (e.g., an anti-PVRIG antibody). In a further embodiment, the immune modulator is an ICOS agonist (e.g., an anti-ICOS antibody including, but not limited to feladilimab), a PARP inhibitor (e.g., niraparib, olaparib), or a STING agonist. In a further embodiment, the additional therapeutic agent is cytarabine or a pharmaceutically acceptablel salt thereof. In a further embodiment, the additional therapeutic agent is an anthracycline (e.g., daunorubicin or idarubicin). In a further embodiment, the additional therapeutic agent is a BCL2 inhibitor (e.g., venetoclax). In a further embodiment, the additional therapeutic agent is a tyrosine kinase inhibitor (e.g., imatinib). In a further embodiment, the additional therapeutic agent is azacitidine. In a further embodiment, the additional therapeutic agent is venetoclax in combination with azacitidine. In certain embodiments, the other therapeutic agent is a Bcl-2 inhibitor. In certain embodiments, the other therapeutic agent is a DNA methyltransferase inhibitor. In certain embodiments, the other therapeutic agent is comprises a Bcl-2 inhibitor and a DNA methyltransferase inhibitor. In certain embodiments, the other therapeutic agent is venetoclax, azacitidine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the other therapeutic agent is venetoclax or a pharmaceutically acceptable salt thereof. In certain embodiments, the other therapeutic agent is azacitidine or a pharmaceutically acceptable salt thereof. In certain embodiments, the other therapeutic agent comprises (i) venetoclax or a pharmaceutically acceptable salt thereof and (ii) azacitidine or a pharmaceutically acceptable salt thereof. E. Pharmaceutical Compositions, Dosages, and Dosage Forms For the purposes of administration, in certain embodiments, the ARMs described herein are administered as a raw chemical or are formulated as pharmaceutical compositions. Pharmaceutical compositions disclosed herein include an ARM and one or more of: a pharmaceutically acceptable carrier, diluent or excipient. An ARM is present in the composition in an amount which is effective to treat a particular disease, disorder or condition of interest. The activity of the ARM can be determined by one skilled in the art, for example, as described in the biological assays described below. Appropriate concentrations and dosages can be readily determined by one skilled in the art. In certain embodiments, the ARM is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg. In certain embodiments, the ARM is present in the pharmaceutical composition in an amount of about 0.01 mg to about 300 mg. In certain embodiments, ARM is present in the pharmaceutical composition in an amount of about 0.01 mg, 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, is carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the invention are prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and in specific embodiments are formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Exemplary routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral (e.g., intramuscular, subcutaneous, intravenous, or intradermal), sublingual, buccal, rectal, vaginal, and intranasal. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia. College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings described herein. The pharmaceutical compositions disclosed herein are prepared by methodologies well known in the pharmaceutical art. For example, in certain embodiments, a pharmaceutical composition intended to be administered by injection is prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. In some embodiments, a surfactant is added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system. Traditional antibody therapeutics have several disadvantages that are addressed by the ARMs approach described herein including difficulties in managing adverse events via adjusting dose and dose frequency of administration, challenges in generating antibodies to certain classes of drug targets (e.g., GPCRs, ion channels, and enzymes), and a new cell line for development is required for each new antibody which can be slow and costly. Moreover, different formats of biologics (e.g., bispecifics) can be challenging to manufacture. In contrast, the ARMs approach provides the following advantages: uniting the pharmacology of antibodies with the dose-control of small molecules, dose controlled PK / PD allowing temporal cell depletion, simpler multimerization, and rapid reversal of cell depletion through dosing of the antibody-binding component (e.g., cotinine hapten) which can uncouple therapeutic effects from potential adverse events. F. Definitions The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. As used herein and in the claims , the term “comprising” encompasses “including” or “consisting” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y. The term “consisting essentially of” limits the scope of the feature to the specified materials or steps and those that do not materially affect the basic characteristic(s) of the claimed feature. The term “consisting of” excludes the presence of any additional component(s). The term “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor. The terms “effective amount” and “therapeutically effective amount” refer to an amount of a compound, or antibody, or antigen-binding portion thereof, according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure. The term “alkyl” represents a saturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms. The term “C1-3alkyl” refers to an unsubstituted alkyl moiety containing 1, 2 or 3 carbon atoms; exemplary alkyls include methyl, ethyl and propyl. The term “alkylene” represents a saturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms. The term “C1-3alkylene” refers to an unsubstituted alkyl moiety containing 1, 2 or 3 carbon atoms with two points of attachment; exemplary C1-3alkylene groups include methylene, ethylene and propylene. The term “alkenyl” represents an unsaturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms. The term “C2-6 alkenyl” refers to an unsubstituted alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms; exemplary alkenyls include propenyl, butenyl, pentenyl and hexenyl. The term “alkenylene” represents an unsaturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms. The term “C2-6 alkenylene” refers to an unsubstituted alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms with two points of attachment; exemplary C2-6 alkenylene groups include propenylene, butenylene, pentenylene and hexenylene. The term “cycloalkyl” represents a saturated cyclic hydrocarbon moiety having the specified number of carbon atoms. The term “C3-6cycloalkyl” refers to an unsubstituted cycloalkyl moiety containing 3, 4, 5 or 6 carbon atoms; exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “cycloalkylene” represents a saturated cyclic hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms. The term “C4-6 cycloalkylene” refers to an unsubstituted cycloalkylene moiety containing 4, 5, or 6 carbon atoms with two points of attachment. Exemplary cycloalkylene groups include cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, or cyclohexane-1,4-diyl. The term “cycloalkenylene” represents an unsaturated cyclic hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms. The term “C3-6cycloalkenylene” refers to an unsubstituted cycloalkenylene moiety containing 3, 4, 5, or 6 carbon atoms with two points of attachment. The term “heterocycloalkylene” refers to a saturated cyclic hydrocarbon moiety containing 1 or 2 heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms. The term “3- to 6-membered heterocycloalkylene” refers to a 3- to 6-membered saturated cyclic moiety containing 2, 3, 4 or 5 carbon atoms in addition to 1 or 2 oxygen, sulphur or nitrogen atoms, with two points of attachment. Suitably, the 3- to 6-membered heterocycloalkylene group contains 1 oxygen or nitrogen atom. Suitably such group contains 3 carbon atoms and 1 oxygen or nitrogen atom, such as azetidindiyl or oxetandiyl. Suitably such group contains 4 or 5 carbon atoms and 1 oxygen or nitrogen atom, such as tetrahydrofurandiyl, tetrahydropyrandiyl, pyrrolidindiyl or piperidindiyl. The term “bridged bicyclic cycloalkylene” refers to a saturated bicyclic hydrocarbon moiety having at least one bridge, with two points of attachment. A “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). The two points of attachment can be from the same or different carbon atoms. The term “C7-9 bridged bicyclic cycloalkylene” refers to an unsubstituted bridged bicyclic cycloalkylene moiety containing 7, 8, or 9 carbon atoms with two points of attachment. The term “arylene” refers to a monocyclic or bicyclic ring system wherein at least one ring in the system is aromatic, with two points of attachment. Exemplary arylene groups include phenylene, biphenylene, naphthylene, and anthracylene. The term “heteroarylene” refers to a monocyclic or bicyclic ring system wherein at least one ring in the system is aromatic, and having, in addition to carbon atoms, from one to five heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment. The term “5- to 6-membered heteroarylene” refers to a 5- to 6-membered cyclic aromatic moiety containing 2, 3, 4 or 5 carbon atoms in addition to 1, 2, or 3 heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment. The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula (I). The invention is further directed to free or unsalted compounds of Formula (I). The salts, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art. Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p- toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, trifluoroacetate, undecanoate, undecylenate, and valerate. Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N′-dibenzylethylenediamine), b / s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolidine-1′-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc. The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers. Divalent groups are groups having two points of attachment. For all divalent groups, unless otherwise specified, the orientation of the group is implied by the direction in which the formula or structure of the group is written. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any compositions and methods similar or equivalent to those described herein can be used in the practice or testing of the methods of the disclosure, exemplary compositions and methods are described herein. Any of the aspects and embodiments of the disclosure described herein may also be combined. For example, the subject matter of any dependent or independent claim disclosed herein may be multiply combined (e.g., one or more recitations from each dependent claim may be combined into a single claim based on the independent claim on which they depend). Ranges provided herein include all values within a particular range described and values about an endpoint for a particular range. Concentrations described herein are determined at ambient temperature and pressure. This may be, for example, the temperature and pressure at room temperature or in a particular portion of a process stream. Preferably, concentrations are determined at a standard state of 25 ºC and 1 bar of pressure. As used herein, the terms “subject” and “patient” refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls. EXAMPLES The following examples illustrate the invention. These Examples are not intended to limit the scope of the invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention. While particular embodiments of the invention are described, the skilled artisan will appreciate that various changes and modifications can be made. EXAMPLE 1: Antibody Dependent Cellular Cytotoxicity Reporter Assay ARMs compounds of Formula (I) can be tested for ADCC activity according to the procedure described below. An antibody dependent cellular cytoxocity reporter assay is conducted using the following four assay components: (i) ARM compound of Formula (I) targeting CCR2 (concentrations ranging from 1 pM to 10 µM) (ii) anti-cotinine antibody having a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12 (rabbit variable region with human IgG1 Fc domain containing a DE mutation (S239D / I332E)) (concentrations ranging from 0.01 µg / mL to 200 µg / mL); (iii) target cells: CHOK1 cells engineered to overexpress either human CCR2 (typically 1000-20,000 cells per well) and (iv) reporter cells: Jurkat cells engineered to express FcγRIIIa with the reporter gene luciferase under the control of the NFAT promoter (typically 3000-75,000 cells per well). Reagents are combined in a final volume of 20 µL in a 384 - well tissue culture treated plate. All four assay components are incubated together for about 12-18 hours. Thereafter, BioGlo Detection reagent (Promega) is added to the wells to lyse the cells and provide a substrate for the luciferase reporter protein. Luminescence signal is measured on a microplate reader and signal:background is calculated by dividing the signal of a test well by the signal obtained when no heterobivalent compound of Formula (I) is added. EC50 calculations are done using Graphpad Prism Software, specifically a nonlinear regression curve fit ( Y = Bottom + ( Top - Bottom ) / ( 1 + 10 ^ ( ( Log EC50 - X ) * HillSlope ) ) ). EXAMPLE 2: Evaluation of Correlation Between Chemokine Receptor 2 (CCR2) Expression and Overall Survival of Acute Myeloid Leukemia (AML) patients A correlation between Chemokine Receptor 2 (CCR2) expression and overall survival of acute myeloid leukemia (AML) patients was evaluated. Analysis of the cancer genome atlas (TCGA) for CCR2 expression in AML patients revealed that higher CCR2 expression is associated with worse prognosis. Specifically, patients with high CCR2 expression had a 12- month survival probability of 0.4 compared to low CCR2 expression patients which had a 12- month survival probability of 0.63. Experimental procedures and results are described in more detail below. Patients with RNA-seq transcriptomics in The Cancer Genome Atlas (TCGA) were identified and thereafter restricted to those with a primary diagnosis of acute myeloid leukemia (encompassing patients with: a) t(8;21)(q22;q22); RUNX1-RUNX1T1 b) NOS c) mutated NPM1 d) myelodysplasia-related changes e) mutated CEBPA f) CBF-beta / MYH11 g) inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 h) minimal differentiation i) maturation j) t(6;9)(p23;q34); DEK-NUP214 k) t(9;11)(p22;q23); MLLT3-MLL and l) without maturation). Altogether this yielded samples from 3594 patients. Right censored (i.e., patients that were alive at the time of data collection) were ignored, as TCGA clinical data only provided information on age and how many days after diagnosis the patient died, but did not specify days after diagnosis for cases in which the patient was still reported to be alive. As such, data was considered from 1237 out of the 3594 patients for which the number of days until death after diagnosis was reported. CCR2 expression data were transformed before any statistical testing. Using the FPKM unstranded counts, counts were log10 transformed with a pseudocount of 0.0029 (the minimum value among samples with non-zero FPKM counts), median centered, and scaled by the standard deviation. With these datasets we then conducted two analyses to assess the relationship between patient survival and CCR2 expression. First, the relationship between CCR2 expression and survival without considering the influence of other covariates was assessed. Patients expressing CCR2 at levels of the 85thpercentile or greater were defined as high expressers (186 patients). Patients expressing CCR2 at levels of the 15thpercentile or lower were defined as low expressers (186 patients). Kaplan- Meier survival curves were then generated for all patients, high CCR2 expressers, and low CCR2 expressers (FIG. 1). FIG.2 shows Kaplan-Meier survival curves for only high and low CCR2 patient groups. Thereafter, we assessed whether pairs of these survival curves differed under a two-sided log rank test and null hypothesis that the survival curves were the same. The log rank test for the high CCR2 expressing patient survival curve vs. all patient survival curve yielded a p-value of 1.568-5, and directionally higher CCR2 was associated with worsened survival. The log rank test for the high CCR2 expressing patient survival curve vs. low CCR2 expressing patient survival curve yielded a p-value of 3.143-7, and directionally higher CCR2 was associated with worsened survival. The log rank test for the low CCR2 expressing patient survival curve vs. all patient survival curve yielded a p-value of 0.0085, and directionally lower CCR2 was associated with improved survival. Altogether, these results suggested higher CCR2 expression was associated with worsened patient survival in AML. Next, the relationship between CCR2 expression and survival was assessed while considering the influence of sex and age of diagnosis as covariates. To do this, a Cox Proportional Hazards model was used to describe the relationship between the covariates and survival. Age of diagnosis was measured in days and gender was binarized such that 0 corresponded to male and 1 corresponded to female. CCR2 expression input to the model was transformed as described above. The fit model (FIG.3) had a concordance of 0.55 suggesting the model explained survival better than random, though there remained a large portion of variance that was unexplained. The fit model yielded point estimates of 0, -0.05, and 0.15 for the coefficients corresponding to age at diagnosis, gender, and transformed CCR2 expression, respectively. The p-values for each coefficient were 0.24, 0.43, and 3.51-7for age at diagnosis, gender, and transformed CCR2 expression, respectively. Thus, at an alpha threshold of 0.05, the null hypothesis that CCR2 expression has no association with survival was rejected. As death events were coded as 1s, this suggested high CCR2 expression was associated with worsened survival. The 95% confidence interval on the estimate of the CCR2 coefficient was [0.09, 0.21], which corresponded to a range of a [1.094, 1.234] multiplicative increase in the relative probability of death for a unit increase in transformed CCR2 expression. Repeating this analysis with TPM unstranded counts (instead of FPKM unstranded counts) yielded a point estimate of 0.15 for the CCR2 coefficient and an associated p-value of 8.837-7. This suggested our findings of CCR2 association with survival were insensitive to the transcript count normalization method used. Altogether, these results suggested higher CCR2 expression is associated with worsened survival. EXAMPLE 3: Analysis of CCR2 Expression on Primary Human AML PBMC Samples CCR2 expression on primary human acute myeloid leukemia (AML) peripheral blood mononuclear cell (PBMC) samples was evaluated. In this analysis, AML cells were differentiated from healthy cells via flow cytometry and described here as the pathogenic cell (PC) population. AML cells of monocytic lineage were differentiated from the total pathogenic cell population using CD14 as a marker of monocytic lineage AML. Finally, the monocytic lineage subset was further evaluated for CCR2 expression. AML cells from 29 donors were analyzed for expression of CD14 and CCR2. CD14 is a marker of human monocytes and the donor samples were classified as having <20% monocytes, 20-40% monocytes or >40% monocytes. The percentage of CD14 positive tumor cells in AML samples ranged from 0.1% to 90.3% across all patient samples tested, with 8 / 29 (28%) having greater than 40% of pathogenic cells with a monocytic lineage. Analysis of CCR2 expression revealed high expression on AML with high levels of monocytic lineage (CD14+) pathogenic cells. In general, there was a positive correlation between the CD14 and CCR2 expression. These data revealed that the patients most likely to benefit from a CCR2 targeted therapy are those patients with myelomonocytic / monocytic AML. Part I – Experimental Procedures CCR2 Expression on human AML PBMCs by FACs Flow cytometry Human AML PBMC samples were analyzed for CCR2 expression via flow cytometry. PBMC samples were thawed, counted, and 2 x 10e6 cells per sample were transferred to 15 mL centrifuge tubes. Samples were rinsed with PBS and centrifuged at 300 g for 10 min. PBMCs were then incubated for 15 minutes at RT in a viability dye solution (BV510, bioscience cat#564406) at 1:1000 dilution. After incubation, cells were spun at 300 g for 10 min, supernatant was discarded, and cells were resuspended in MACs buffer. Antibody cocktail containing anti- CCR2 (see Table 3) was prepared in brilliant buffer and added to the cell solution. Cells were incubated in the dark for 30 minutes. After incubation, cells were washed with MACs buffer and spun at 400g for 10 min. Cells were then resuspended in 400 µL MACs buffer and kept at 4 °C in the dark until sample acquisition. Samples were run on X and data were analyzed using BD FACSDiva 8.0.1 and FlowJo 10.10. Table 3 - CCR2 Staining Panel. Antibody cocktail prepared in Brilliant Buffer.Gating StrategyHuman PBMCs were identified via FSC-A x SSC-A. Live PBMCs were identified via SSC-A x V500-C-A. Pathological cells (PCs) were identified via SSC-A x BV605 (CD45) and definedas mononuclear cells, excluding red blood cells and lymphocytes. CD14 expression was confirmed via SSC-A x PE-CD14 and CCR2 expression was confirmed via SSC-A x APC. FIG.4 summarizes the gating strategy. Data Analysis The total AML cell population was first evaluated to determine the percentage of PCs that were monocytic lineage AML, or CD14-positive. Next, the PCs were grouped into three categories: <20% monocytic, 20-40% monocytic, and >40% monocytic. Lastly, CCR2 expression was evaluated for the entire PC population. Part II – Results Pathogenic AML cells (CD45+ mononuclear cells, excluding lymphocytes) from 29 donors were analyzed for expression of CD14 and CCR2. CD14 is a marker of human monocytes and the donor samples were classified as having <20% monocytes, 20-40% monocytes or >40% monocytes. The percentage of CD14 positive tumor cells in AML samples ranged from 0.1% to 90.3% across all patient samples tested with 8 / 29 (28%) having greater than 40% of pathogenic cells of monocytic lineage. Analysis of CCR2 expression revealed high expression on patients with high levels of monocytic lineage (CD14+) pathogenic cells (FIG.5). In general, there was a positive correlation between the CD14 and CCR2 expression (Table 4). These data revealed that the patients most likely to benefit from a CCR2 targeted therapy are those patients with myelomonocytic / monocytic AML. More generally, patients with AML that have an elevated amount of monocytes are more likely to receive greater benefit from a CCR2 targeted therapy, such as using a compound described herein. Table 4 - Percent of Pathological Cells expressing CD14 and CCR2.

[0006] EXAMPLE 4: Profiling of CCR2 Expression in Patients with Acute Myeloid Leukemia and Chronic Myelomonocytic Leukemia Expression of the Chemokine Receptor 2 (CCR2) on malignant cells from Bone Marrow Mononuclear Cells (BMMCs) and Peripheral Blood Mononuclear Cells (PBMCs) from patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) was evaluated. Primary bone marrow and peripheral blood AML samples were sourced from OncoPrecision’s Cells and Tissue Bio-Collection (CTBC). AML cells were differentiated from healthy cells via flow cytometry (CD45 vs SSC gating). AML subtypes were further differentiated using markers CD45, CD11b, CD34, CD117, and CCR2. Primary human CMML PBMC samples were obtained and flow cytometry was used to identify MO1 monocytes and CMML cells were further differentiated using markers CD45, CD11b, CD34, CD117, and CCR2. As shown in FIG.6, the percentage of CCR2 positive tumor cells in AML samples ranged from 2.4% to 97.1% across different AML subtypes with primitive forms of AML (M0, M1, M2) expressing low levels of CCR2, myelomonocytic AML (M4) moderate to high levels of CCR2, and monocytic AML (M5) expressing high levels. Analysis of CCR2 expression in subpopulations of AML cells revealed a high and homogeneous expression of CCR2 on CD11b+ AML cells and generally low expression on CD34+ blasts, with the exception of M4 subtypes of AML, which in some cases exhibited CD34+ CCR2+ co-expression. In 3 / 3 (100%) CMML samples, CCR2 was highly expressed on the MO1 monocytes. The CMML samples exhibited CCR2 expression between 73 and 97% on the malignant populations of cells. These results demonstrated high and homogenous CCR2 expression on malignant populations in AML and CMML. EXAMPLE 5: Monocyte Depletion and Profiling of Primary Human Chronic Myelomonocytic Leukemia (CMML) Peripheral Blood Mononuclear Cell (PBMC) Samples Experiments were performed to evaluate ex vivo treatment of CMML patient-derived cells with the following combination (hereinafter “Test Article”): (i) an anti-cotinine antibody that has S239D / I332E mutations in the human IgG1 constant region to enhance FcγR binding and (ii) CCR2-CyTaC compound 36. Compound 36 has the chemical structure: CMML malignant monocytes were defined utilizing CD45 staining and side scatter to exclude red blood cells and lymphocytes. CCR2 expression was analyzed on the CD14 positive subset and CCR2 positivity ranged from 12.6% to 96.1% within the CD14 positive monocytes. (FIG. 9). Pathogenic cell depletion, in the presence of CCR2-CyTaC and S,S-cotinine carboxamide antibody, was evident when measured as depletion of the CD14+ pathogenic cells (FIG.10) and when measured as depletion of CCR2+ / CD14+ pathogenic cells (FIG.11). In all CMML donor samples depletion of CCR2+ target cells was observed, ranging from 58.6% to 90.9% depletion. These data demonstrated that CCR2 is highly expressed within monocyte populations of CMML donor samples and that in the presence of Test Article, CCR2-expressing pathogenic cells are depleted. Experimental procedures and results are described in more detail below. Part I – Experimental Procedures Primary Cell Information Fresh whole blood from CMML patients was sent to DLS-Seattle and PBMCs were isolated and frozen on site at DLS-Seattle (Table 5). Limited information about the patient samples was provided and patient history and / or pathology reports were provided for only few patients to confirm the diagnosis of CMML. Based on the prior treatment history information, it is likely that sample from CMML donor 7 was actually from a patient with CML (chronic myeloid leukemia) based on treatment with sprycel and tasigna (tyrosine kinase inhibitors) – both standards of care for CML but not CMML. Because of this CMML Donor 7 was excluded from some of the analyses below. Past medical history or pathology report were not available for CMML Donors 4 and 5. CMML Donor 6 had a concurrent diagnosis of mastocytosis. Table 5 - Human CMML Whole Blood Samples. ε Secondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. Reagents Table 6 – Reagents. Test article was diluted in RPMI-1640 + 10% ultra-low IgG FBS + 1% GlutaMax + 1% Sodium Pyruvate. CCR2 Expression on human CMML PBMCs by FACS Flow Cytometry Patient CMML PBMC samples were analyzed for CCR2 expression and subsequent monocyte depletion via flow cytometry. S,S-cotinine carboxamide antibody and CCR2-CyTaC compound 36 were diluted in assay media (RPMI-1640 + 10% ultra-low IgG FBS + 1% GlutaMax + 1% Sodium Pyruvate) at a concentration of 100nM and 100nM, respectively, and 25µL of each were added to the corresponding wells of a 96 well plate. PBMC samples were thawed, counted, and diluted to 2 x 10e6cells in assay media.50µL of diluted PBMCs were added to the plate. The plate was centrifuged for 1 minute at 500 rpm and incubated at 37°C with 5% CO2for 24 hours.After incubation, plates were centrifuged at 1500 rpm for 8 minutes and cells were resuspendedin 100µL of PBS + 2% ultra-low IgG FBS.2µL of 6.25µg human Fc block was added to the wells of the plate, centrifuged for 1 min at 500rpm and incubated at RT for 15 minutes.5µL of viability dye and 3 µL each of diluted CCR2-PE, CD45-FITC, and CD14-PC7 were added to the plate. The plate was then centrifuged for 1 minute at 500 rpm and incubated for 30 minutes in the dark at 4-8°C. After incubation, cells were spun at 1500 rpm for 8 minutes and resuspended in 100µL 2% PFA fixation buffer. Samples were incubated for 20 minutes in the dark, at 4-8°C. After incubation, cells were centrifuged and resuspended in 150µL of PBS + 2% ultra-low IgG FBS buffer. Samples were run on CytoFlex S collecting all events in each well and data was analyzed using FlowJo 10.10. Gating Strategy Human PBMCs were identified via FSC-A x SSC-A. Live PBMCs were identified via SSC-H x APC-H (Cell Trace Far Red). CD45+ cells were identified via FSC-H x FITC-H. CD14+ cellswere identified via FSC-H x PC7-H. CCR2 expression was identified via FSC-H x PE-A. The gating strategy is shown in FIG.7. Data Analysis Data Analysis was performed using FlowJo Version 10.1.0.0. Monocyte depletion was calculated by: Part II – Results Frequency of CD14+ Monocyte Populations Among CMML Donors The distribution of CD14+ monocyte populations among CD45+ immune cells was determined for human CMML donors, ranging from 8.8% to 62.2% in CMML donors (FIG.8 and Table 7) Table 7 - Percentage of CD14+ Cells within CD45+ Cells of CMML Donors

[0007] ε Secondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. CCR2 Expression Among CMML Donors CCR2 expression within CD14+ monocyte populations were identified across six human CMML PBMC samples (FIG.9). CCR2 expression ranged from 12.6% to 96.1% within the CD14+ monocyte cells (Table 8). Table 8 - Percentage of CD14+ Cells expressing CCR2 of CMML Donors *Reported as an average of 3 samples across the same donor;εSecondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient; ND = not determined, CCR2 expression was not tested in this donor. Percent Monocyte Depletion Among CMML Donors Monocyte depletion was observed across 7 different CMML PBMC donors. In the presence of both S,S-cotinine carboxamide antibody and CCR2-CyTaC compound 36, CMML donors demonstrated monocyte depletion to a varying degree. When gating on CD14+ monocytes, monocyte depletion was demonstrated in 6 of 6 CMML donors (excluding donor 7), ranging from 23.0 ± 1.3% to 41.0 ± 7.3% (FIG. 10, Table 9). When gating on the CCR2+ monocytes, monocyte depletion was demonstrated in 5 of 5 CMML donors for which CCR2 staining was performed (excluding donor 7), ranging from 66.0 ± 10.2% to 90.9 ±2.6% (FIG.11, Table 10). Table 9 - Percent CD14+ Monocyte Depletion Among CMML Donors in the Presence of S,S Cotinine Carboxamide Antibody and CCR2-CyTaC. *Reported as an average and SD of 3 samples across the same donor;εSecondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient. Table 10 - Percent CCR2+ Monocyte Depletion Among CMML Donors in the Presence of S,S-Cotinine Carboxamide Antibody and CCR2-CyTaC. *Reported as an average and SD of 3 samples across the same donor;εSecondary evaluation of donor treatment history suggested that this donor was being treated for CML and may have been misrepresented as a CMML patient; ND: not determined, CCR2 staining was not performed on this donor. The aim of this experiment was to assess CCR2 expression on human primary CMML samples and ex vivo depletion when treated with Test Article. CMML PBMC samples were incubated with Test Article at a concentration of 100nM (with respect to both components of the Test Article) for 24 hours and monocyte depletion was assessed via flow cytometry. CCR2 expression was confirmed via flow cytometry. Within CMML PBMCs, the distribution of CD14-positive monocytes ranged from 8.8% to 62.2% among the CD45+ immune cell population. Within the CD14-positive monocyte population, CCR2 expression ranged from 12.6% to 96.1% (Table 8). Across the CMML PBMC donors, monocyte depletion was evaluated after a 24-hour incubation with S,S-cotinine carboxamide antibody and CCR2-CyTaC. When gating on CD14+ monocytes, monocyte depletion was observed in all CMML donors (excluding donor 7), ranging from 23.0 ± 1.3% to 41.0 ± 7.3% (FIG. 10). When gating on the CD14+CCR2+ monocytes, monocyte depletion was observed in 5 of the 5 CMML donors (excluding donor 7 and data on donor 1 was not collected), ranging from 66.0 ± 10.2% to 90.9 ±2.6% (FIG.11). Overall, these data demonstrated that CCR2 is expressed within monocyte populations of CMML donors and that CCR2+ monocytes are depleted following treatment with Test Article. EXAMPLE 6: Evaluation of Ex-Vivo Activity of Anti-cotinine Antibody in Combination with Heterobifunctional CyTAC in AML and CMML Patient Derived Cells Experiments were conducted to evaluate ex vivo treatment of AML and CMML patient- derived cells with the following combination of anti-cotinine antibody and heterobifunctional CyTAC molecule (hereinafter “Test Article”): ^ an anti-cotinine antibody of the IgG1 isotype having a heavy chain and a light chain, wherein the heavy chain comprised a heavy chain variable region (VH) having SEQ ID NO: 7, the light chain comprised a light chain variable region (VL) having SEQ ID NO: 8, wherein the antibody had a substitution in the Fc region to increase or enhance ADCC activity, wherein the substitution was S239D / I332E, where residue numbering is according to the EU Index. ^ a heterobifunctional CyTAC molecule that is compound 36, which has the following chemical structure:

[0008] Experiments were also conducted using Test Article in combination with venetoclax (Ven) and azacitidine (Aza). Primary bone marrow and peripheral blood AML samples were sourced, and AML cells were differentiated from healthy cells via flow cytometry (CD45 vs SSC gating). AML subtypes were further differentiated using markers CD45, CD11b, CD34, CD117, and CCR2. Primary human CMML PBMC samples were obtained, and flow cytometry was used to identify MO1 monocytes. CMML cells were further differentiated using markers CD45, CD11b, CD34, CD117, and CCR2. To evaluate the activity of Test Article in AML, OncoPrecision's Patient Micro-Avatar (PMAs) technology was employed. This platform promotes the ex-vivo survival of Patient Derived Cells (PDCs) by mimicking the cancer microenvironment through the co-culture with heterologous stromal cells. As such, PMAs allow the simultaneous tracking of pathological and healthy cells using cluster differentiation markers and multiparametric flow cytometry. Heterologous NK cells are also added to the PMA system at a 1:1 target to effector ratio. First, PMAs from 15 AML samples profiled for CCR2 expression were treated with Test Article and the depletion of AML cells, mediated by Fc gamma receptor 3a positive (FcγRIIIa) natural killer cells, was assessed. The results showed a robust activity of Test Article in the CD11b+ malignant population in 12 of the 15 (80%) AML patient samples evaluated with typical potencies of ~10nM based on full curve analysis and a range of 39.5-71.6% target cell killing. The results also showed a robust activity of Test Article in the overall AML cell population in 4 of the 15 (27%) AML patient samples. The responding patients all fell into either the M4 or M5 Fab classification and CCR2 profiling indicated expression levels >40% of tumor cells in all responders. The lack of robust activity in the remainder of the cohort can be partially explained by dominance of CCR2 negative AML populations such as CD34+ blasts. Second, PMAs from the 3 CMML samples profiled for CCR2 expression were treated similarly and the results showed robust activity of Test Article in the MO1 monocyte population on 3 of the 3 (100%) samples evaluated and a range of 36-61% target cell killing. Next, Aza+Ven alone or Test Article combined with Aza+Ven were evaluated in the same 15 AML samples and the depletion of tumor cells was assessed. In 9 / 15 (60%) of AML patient samples, the combination outperformed the single agents alone. Test Article outperforms Aza+Ven in targeting differentiated monocytic cells, while Ven-Aza outperformed Test Article in targeting undifferentiated blasts. Therefore, the improved therapeutic outcome of the combination of Test Article and Aza+Ven could be attributed to the differential targeting of subpopulations of AML cells. PMAs from the 3 CMML samples were treated similarly and the results showed minimal therapeutic effect of Aza +Ven as a single agent or combined with Test Article. This can be explained by the homogenous CCR2+ cell population in CMML and a lack of CMML cell populations that are responsive to Aza + Ven. The results demonstrated that the high and homogenous CCR2 expression on malignant populations drives Test Article activity, ex vivo human target engagement, and pharmacodynamic activity of Test Article. Furthermore, it supported the benefit of single agent efficacy of Test Article in myelomonocytic / monocytic AML and CMML, as well as the value of combining Test Article with Aza+Ven in earlier lines of AML treatment. FIG. 12A and FIG. 12B show the impact of heterologous NK cells on CCR2-CyTaC platform activity. FIG. 12A is a heatmap representing the AUC for the CCR2-CyTAC dose- response in the CD45 / CD11b double positive population, comparing results in the absence and presence of heterologous NK cells. FIG.12B is a graph showing CCR2-CyTAC platform activity (AUCinv) across the CD45 / CD11b double positive population of all the patients in the cohort (n=18). FIG. 13A and FIG.13B show the enhanced response to combined treatment of CCR2- CyTaC platform and Aza+Ven. FIG.13A is a heatmap of CCR2-CyTAC activity over total PCs. FIG. 13B is a boxplot comparing treatment activity on PCs. p-value = 0.0152. *Corresponds to CMML samples. EXAMPLE 7: Administration of Anti-cotinine Antibody in Combination with Heterobifunctional CyTAC to Cynomolgus Monkeys Experiments were conducted where the following combination of anti-cotinine antibody and heterobifunctional CyTAC molecule (hereinafter “Test Article”) was administered to cynomolgus monkeys: ^ an anti-cotinine antibody of the IgG1 isotype having a heavy chain and a light chain, wherein the heavy chain comprised a heavy chain variable region (VH) having SEQ ID NO: 7, the light chain comprised a light chain variable region (VL) having SEQ ID NO: 8, wherein the antibody had a substitution in the Fc region to increase or enhance ADCC activity, wherein the substitution was S239D / I332E, where residue numbering is according to the EU Index. ^ a heterobifunctional CyTAC molecule that is compound 1, which has the following chemical structure: . Pharmacokinetic (PK) and pharmacodynamic (PD) effects on CCR2 MO1 monocytes in vivo were evaluated. Test Article demonstrated PK supportive of dosing in human subjects. In 9 / 9 (100%) animals, Test Article effectively depleted >95% of CCR2+ monocytes which returned after drug levels dropped below ~10 ng / mL. All doses were well tolerated and the findings of comprehensive immunophenotyping were acceptable. EXAMPLE 8: Evaluation of Ex-Vivo Activity of Anti-cotinine Antibody in Combination with Heterobifunctional CyTAC in AML Patient Derived Cells Experiments were conducted to evaluate the performance of anti-cotinine antibody in combination with a heterobifunctional CyTAC in treating different types of acute myeloid leukemia. In particular, the anti-cotinine antibody in combination with a heterobifunctional CyTAC was tested for performance in treating (a) primitive acute myeloid leukemia and (b) monocytic acute myeloid leukemia. Ability of the anti-cotinine antibody in combination with a heterobifunctional CyTAC to kill lymphocyte cells was also tested. Procedures & Results Experiments were conducted to evaluate ex vivo treatment of AML patient-derived cells with the following combination of anti-cotinine antibody and heterobifunctional CyTAC molecule (hereinafter “Test Article”): ^ an anti-cotinine antibody of the IgG1 isotype having a heavy chain and a light chain, wherein the heavy chain comprised a heavy chain variable region (VH) having SEQ ID NO: 7, the light chain comprised a light chain variable region (VL) having SEQ ID NO: 8, wherein the antibody had a substitution in the Fc region to increase or enhance ADCC activity, wherein the substitution was S239D / I332E, where residue numbering is according to the EU Index. ^ a heterobifunctional CyTAC molecule that is compound 36, which has the following chemical structure: The patient-derived cells were (a) primitive acute myeloid leukemia cells, (b) monocytic acute myeloid leukemia cells, and (c) lymphocyte cells. Experiments were also conducted to test the ability of the following to kill (a) primitive acute myeloid leukemia cells, (b) monocytic acute myeloid leukemia cells, and (c) lymphocyte cells: ^ Venetoclax (Ven) in combination with azacitidine (Aza); and ^ Test Article in combination with venetoclax (Ven) and azacitidine (Aza). Primary bone marrow and peripheral blood AML samples were sourced, and AML cells were differentiated from healthy cells via flow cytometry (CD45 vs SSC gating). AML subtypes were further differentiated using markers CD45, CD11b, CD34, CD117, and CCR2. To evaluate the activity of Test Article in killing the indicated cell types, OncoPrecision's Patient Micro-Avatar (PMAs) technology was employed. This platform promotes the ex-vivo survival of Patient Derived Cells (PDCs) by mimicking the cancer microenvironment through the co-culture with heterologous stromal cells. As such, PMAs allow the simultaneous tracking of pathological and healthy cells using cluster differentiation markers and multiparametric flow cytometry. Heterologous NK cells are also added to the PMA system at a 1:1 target to effector ratio. First, PMAs from 15 AML samples profiled for CCR2 expression were treated with Test Article and the depletion of AML cells, mediated by Fc gamma receptor 3a positive (FcγRIIIa) natural killer cells, was assessed. Cell killing results using the Test Article alone are shown in Figure 14. Results in Figure 14 show that the Test Article was much more effective in killing monocytic acute myeloid leukemia cells compared to either primitive acute myeloid leukemia cells or lymphocyte cells. Next, Aza+Ven alone or Test Article combined with Aza+Ven were evaluated in the same 15 AML samples and the depletion of tumor cells was assessed. Results are shown in Figure 15, Comparison of results shown in Figures 14 and 15 show, for example, that: ^ Test Article resulted in superior killing of monocytic acute myeloid leukemia cells compared to venetoclax (Ven) in combination with azacitidine (Aza); and ^ Use of Test Article in combination with venetoclax (Ven) and azacitidine (Aza) resulted in superior killing of monocytic acute myeloid leukemia cells compared to use of either (i) Test Article alone or (ii) venetoclax (Ven) in combination with azacitidine (Aza). EXAMPLE 9: Evaluation of Ex-Vivo Activity of Anti-cotinine Antibody in Combination with Heterobifunctional CyTAC in Acute Myelomonocytic Leukemia (AMML) Human Patient Derived Cells Experiments were conducted to evaluate the performance of anti-cotinine antibody in combination with a heterobifunctional CyTAC in treating acute myelomonocytic leukemia (AMML). Experimental procedures and results are provided below. Part I – Experimental Procedures Acute myelomonocytic leukemia cells (CD45+ CD11b+) obtained from a human patient with acute myelomonocytic leukemia where exposed ex vivo to anti-cotinine antibody in combination with increasing concentrations of CyTAC (where the anti-cotinine antibody in combination with the CyTAC are referred to as Test Article), and then analyzing to determine the percentage of cells that remained, which provides a measure of the cells that were killed by the Test Article. The Test Article was following combination of anti-cotinine antibody and heterobifunctional CyTAC molecule: ^ an anti-cotinine antibody of the IgG1 isotype having a heavy chain and a light chain, wherein the heavy chain comprised a heavy chain variable region (VH) having SEQ ID NO: 7, the light chain comprised a light chain variable region (VL) having SEQ ID NO: 8, wherein the antibody had a substitution in the Fc region to increase or enhance ADCC activity, wherein the substitution was S239D / I332E, where residue numbering is according to the EU Index. ^ a heterobifunctional CyTAC molecule that is compound 36, which has the following chemical structure: A control arm of the experiment entailed exposing control cells (which were CCR2- negative stromal cells) ex vivo to anti-cotinine antibody in combination with increasing concentrations of CyTAC (where the anti-cotinine antibody in combination with the CyTAC are referred to as Test Article), and then analyzing to determine the percentage of cells that remained, which provides a measure of the cells that were killed by the Test Article. Part II – Results Results are shown in Figure 16, which shows the percentage of cells that remained at different concentrations of CyTAC, which provides a measure of the cells that were killed by the Test Article. Results in Figure 16 show that the Test Article potently kills acute myelomonocytic leukemia cells (CD45+ CD11b+) obtained from the human patient with acute myelomonocytic leukemia. EXAMPLE 10: Evaluation of Ex-Vivo Activity of Anti-cotinine Antibody in Combination with Heterobifunctional CyTAC Towards Additional Heme Malignancy Cell Lines The potent ability of anti-cotinine antibody in combination with heterobifunctional CyTAC to treat chronic myelomonocytic leukemia (CMML), myelomonocytic acute myeloid leukemia, and monocytic acute myeloid leukemia demonstrated by experimental results herein above is a unique feature. Such potent ability of the anti-cotinine antibody in combination with heterobifunctional CyTAC to treat chronic myelomonocytic leukemia (CMML), myelomonocytic acute myeloid leukemia, and monocytic acute myeloid leukemia is contrasted by the following: ° an activity profile ranging from limited ability to no ability for the anti-cotinine antibody in combination with a heterobifunctional CyTAC to kill heme malignancy cells from the following cell lines: Raji, K562, Jurkat, SU-DHL-1, and KU812. The heme malignancy cell lines Raji, K562, Jurkat, SU-DHL-1, and KU812 have little to no expression of CCR2 on the cell. Experimental procedures and results evaluating ability of anti- cotinine antibody in combination with heterobifunctional CyTAC to kill heme malignancy cells from the cell lines Raji, K562, Jurkat, SU-DHL-1, and KU812 are provided below. Part I – Experimental Procedures Cell lines were acquired from ATCC. Cells were grown in media containing RPMI 1640 (Gibco), 10% FBS(Gibco) and 1% penicillin / streptomycin (Gibco). Cells were plated at 1 x 106 cells / mL and were transduced at an MOI of 5 with GFP Nuclight Green lentivirus (Sartorius). Cells were incubated 24 hours at 37oC before selection with 1 ^g / mL Puromycin. Cells were selected for one week before being maintained in 0.1 ^g / mL Puromycin. Target cells were plated in a 96 well flatbottom plate at a density of 2 x 104 cells per well in RPMI+10% FBS. Human effector NK cells (Stemcell) were plated at a 1 x 105 cells per well in RPMI+10% FBS. Compound II-1 (40 nM final concentration) was mixed with Test Antibody (20 nM final concentration, ADCC enhanced antibody) and the resulting mixture was added to the cells. Cells were incubated for 24 hours and imaged on the Incucyte. GFP cells were counted and cell depletion was calculated compared to an antibody only control. The CyTAC molecule, compound II-1, used in this experiment had the following chemical structure: . The Test Antibody used in this experiment was an an anti-cotinine antibody of the IgG1 isotype having a heavy chain and a light chain, wherein the heavy chain comprised a heavy chain variable region (VH) having SEQ ID NO: 7, the light chain comprised a light chain variable region (VL) having SEQ ID NO: 8, wherein the antibody had a substitution in the Fc region to increase or enhance ADCC activity, wherein the substitution was S239D / I332E, where residue numbering is according to the EU Index. Part II – Results Results are shown in Figure 17, which shows percent cell depletion observed when the indicated cells where exposed to Compound II-1 in combination with Test Antibody according to the procedure described above. Results in Figure 17 demonstrate that the anti-cotinine antibody in combination with heterobifunctional CyTAC had an activity profile ranging from limited ability to no ability to kill heme malignancy cells from the following cell lines: Raji, K562, Jurkat, SU-DHL- 1, and KU812. SEQUENCE LISTINGS Heavy chain CDR1 amino acid sequence SEQ ID NO: 1 NYWMS Heavy chain CDR2 amino acid sequence SEQ ID NO: 2 DIHGNRGFNYHASWAKG Heavy chain CDR3 amino acid sequence SEQ ID NO: 3 ADDSGSHDI Light chain CDR1 amino acid sequence SEQ ID NO: 4 QSSQSVYSAKLS Light chain CDR2 amino acid sequence SEQ ID NO: 5 YGSTLAS Light chain CDR3 amino acid sequence SEQ ID NO: 6 QGTFYGPDWYFA Variable heavy chain amino acid sequence SEQ ID NO: 7 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQAPGKGLEWVGDIHG NRGFNYHASWAKGRFTVSRSKNTLYLQMNSLRAEDTAVYYCAKADDSGSHDIW GQGTLVTVSS Variable light chain amino acid sequence SEQ ID NO: 8 DIQMTQSPSSLSASVGDRVTITCQSSQSVYSAKLSWYQQKPGKAPKLLIYYGSTLASGVPSRFS GSGSGTQFTLTISSLQPEDFATYYCQGTFYGPDWYFAFGGGTKVEIK Heavy chain amino acid sequence Light chain amino acid sequence SEQ ID NO 10 Heavy chain amino acid sequence Light chain amino acid sequence Heavy chain amino acid sequence

[0009] Light chain amino acid sequence SEQ ID NO 14

Claims

CLAIMS 1. A method of treating a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, to thereby treat the leukemia, wherein said compound of Formula I is represented byor a pharmaceutically acceptable salt thereof; wherein: R1is C1-4alkyl or C3-6cycloalkyl; R2is hydrogen or C1-4alkyl; R3is hydrogen or C1-4alkyl; L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g), (L-h), (L- i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv):stereoisomer thereof, wherein: Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-;each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-;stereoisomer thereof, wherein: Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -C(O)NR1b-, or -NR1bC(O)-; or L2bis, whereinrepresents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3 alkyl;(L-c), or a stereoisomer thereof, wherein: L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or - C(O)NH-;wherein: L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH- ; ;wherein: L1fis a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)- NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH;wherein: Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; andrepresents a covalent bond to L1g;stereoisomer thereof, wherein: each Z1is independently N or CH; L1his a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-; L2his C2-10linear alkylene or, wherein n is 1, 2, 3, or 4, andrepresents a covalent bond to L1hand represents a covalent bond to L3h;L3his a bond, -C(O)CH2-, -O-(C3-6cycloalkylene)-O-, or - C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or -C(O)CH2-; and m is 1, 2, or 3;wherein: L1iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L3iand represents a covalent bond to NH;L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-;stereoisomer thereof, wherein: Z1is C, CH, or N; each of Z2, Z3, Z4and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene or, wherein n is 1 or 2, andrepresents a covalent bond to L1j; and represents a single bond or a double bond;stereoisomer thereof, wherein:Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH- or -NHC(O)-; and L2kis a C3-8straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k;stereoisomer thereof, wherein: Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH- or -NHS(O)2- ; and L2mis C3-6linear alkylene, C3-6cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;wherein eachrepresents a covalent bond to the NH group of Formula (I), and eachrepresents a covalent bond to the methylene group of Formula (I).

2. A method of depleting C-C motif chemokine receptor 2 (CCR2)-expressing cells in a patient suffering from a leukemia selected from chronic myelomonocytic leukemia, acute myeloid leukemia, or juvenile myelomonocytic leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein said compound of Formula I is represented bypharmaceutically acceptable salt thereof; wherein: R1is C1-4alkyl or C3-6cycloalkyl; R2is hydrogen or C1-4alkyl; R3is hydrogen or C1-4alkyl; L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g), (L-h), (L- i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv):stereoisomer thereof, wherein: Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-;stereoisomer thereof,wherein: Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -C(O)NR1b-, or -NR1bC(O)-; orrepresents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3 alkyl;(L-c), or a stereoisomer thereof, wherein: L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or - C(O)NH-;wherein: L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH- ; ;wherein: L1fis a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)- NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH;wherein: Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L, , , , , represents a covalent bond to L1g;stereoisomer thereof, wherein: each Z1is independently N or CH; L1his a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-; L2his C2-10linear alkylene or, wherein n is 1, 2, 3, or 4, andrepresents a covalent bond to L1hand represents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6cycloalkylene)-O-, or - C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or -C(O)CH2-; and m is 1, 2, or 3;wherein: L1iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bondrepresents a covalent bond to NH;L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-;stereoisomer thereof, wherein: Z1is C, CH, or N; each of Z2, Z3, Z4and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene or, wherein n is 1 or 2, andrepresents a covalent bond to L1j; and represents a single bond or a double bond;stereoisomer thereof, wherein:Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH- or -NHC(O)-; and L2kis a C3-8straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k;stereoisomer thereof, wherein: Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH- or -NHS(O)2- ; and L2mis C3-6linear alkylene, C3-6cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;wherein eachrepresents a covalent bond to the NH group of Formula (I), and eachrepresents a covalent bond to the methylene group of Formula (I).

3. The method of claim 2, wherein the CCR2-expressing cells are myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), neutrophils, macrophages, B regulatory cells (Bregs), CD8 regulatory cells (CD8regs), exhausted T cells, or cancer- associated fibroblasts (CAFs).

4. The method of any one of claims 1-3, wherein R1is -CH3.

5. The method of any one of claims 1-4, wherein R2is isopropyl and R3is methyl.

6. The method of any one of claims 1-4, wherein R2is t-butyl and R3is hydrogen.

7. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-a-i):, wa (L-a).

8. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-a-ii): , wp is 1 or 2; and m is 1 or 2.

9. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-a-iii):-iii), or a stereoisomer thereof, wherein p is 1 or 2; m is 1 or 2; n is 1, 2, or 3; and and are as defined for Formula (L-a).

10. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-a) selected from the group consisting of:

11. The method of any one of claims 1-6, wherein L is a divalent linker represented by12. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-b-i):(L-b-i), or a stereoisomer thereof, wherein L1b, L2b, and are as defined for Formula (L-b); p is 1 or 2; and m is 1or 2.

13. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-b) selected from the group consisting of:

14. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-c-i): (L-c-i), or a stereoisomer thereof, w, and are as defined for Formula (L-c); p is 1 or 2; and m is 1 or2.

15. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-c) selected from the group consisting of:, , ,16. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-d) selected from the group consisting of: , , , ,,17. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-f) selected from the group consisting of: d18. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-g-i): ware as defined for Formula (L-g); Z1, Z2, and Z3are each independently selected from N or CH, provided that one or two of Z1, Z2, and Z3is N.

19. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-g) selected from the group consisting of: , , , ,20. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-h) selected from the group consisting of: ,, ,21. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-i) selected from the group consisting of: , , a22. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-j) selected from the group consisting of: ,O.

23. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-k) selected from the group consisting of: , ,24. The method of any one of claims 1-6, wherein L is a divalent linker of Formula (L-m) selected from the group consisting of:,25. The method of any one of claims 1-3, wherein the compound is selected from a compound as listed in Table 1 or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1-3, wherein the compound isor a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-3, wherein the compound is.

28. The method of any one of claims 1-3, wherein the compound isor a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1-3, wherein the compound is30. The method of any one of claims 1-29, wherein the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously.

31. The method of any one of claims 1-29, wherein the compound and the antibody, or antigen-binding fragment thereof, are administered sequentially.

32. The method of any one of claims 1-31, wherein the leukemia is chronic myelomonocytic leukemia.

33. The method of claim 32, wherein the chronic myelomonocytic leukemia is a dysplastic chronic myelomonocytic leukemia.

34. The method of claim 32, wherein the chronic myelomonocytic leukemia is a proliferative chronic myelomonocytic leukemia.

35. The method of claim 32, wherein the chronic myelomonocytic leukemia is of category CMML-0.

36. The method of claim 32, wherein the chronic myelomonocytic leukemia is of category CMML-1.

37. The method of claim 32, wherein the chronic myelomonocytic leukemia is of category CMML-2.

38. The method of any one of claims 1-31, wherein the leukemia is acute myeloid leukemia.

39. The method of claim 38, wherein the acute myeloid leukemia is an undifferentiated acute myeloblastic leukemia, an acute myeloblastic leukemia with minimal maturation, an acute myeloblastic leukemia with maturation, an acute promyelocytic leukemia, an acutemyelomonocytic leukemia, an acute myelomonocytic leukemia with eosinophilia, an acute monocytic leukemia, or an acute erythroid leukemia.

40. The method of claim 38, wherein the acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 8 and 21 [t(8;21)], or (b) an acute myeloid leukemia with a translocation or inversion in chromosome 16 [t(16;16) or inv(16)].

41. The method of claim 38, wherein the acute myeloid leukemia is (a) an acute myeloid leukemia with the PML-RARA fusion gene, or (b) an acute myeloid leukemia with a translocation between chromosomes 9 and 11 [t(9;11)].

42. The method of claim 38, wherein the acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 6 and 9 [t(6:9)], or (b) an acute myeloid leukemia with a translocation or inversion in chromosome 3 [t(3;3) or inv(3)].

43. The method of claim 38, wherein the acute myeloid leukemia is (a) an acute myeloid leukemia with a translocation between chromosomes 1 and 22 [t(1:22)], or (b) an acute myeloid leukemia with a BCR-ABL1 (BCR-ABL) fusion gene.

44. The method of claim 38, wherein the acute myeloid leukemia is (a) an acute myeloid leukemia with mutated NPM1 gene, or (b) an acute myeloid leukemia a biallelic mutation of the CEBPA gene.

45. The method of claim 38, wherein the acute myeloid leukemia is an acute myeloid leukemia with a mutated RUNX1 gene.

46. The method of claim 38, wherein the acute myeloid leukemia is myelomonocytic acute myeloid leukemia.

47. The method of claim 38, wherein the acute myeloid leukemia is monocytic acute myeloid leukemia.

48. The method of any one of claims 1-31, wherein the leukemia is juvenile myelomonocytic leukemia.

49. The method of claim 48, wherein the juvenile myelomonocytic leukemia is of Category 1.

50. The method of claim 48, wherein the juvenile myelomonocytic leukemia is of Category 2.

51. The method of claim 48, wherein the juvenile myelomonocytic leukemia is of Category 3.

52. The method of claim 48, wherein the patient suffering from juvenile myelomonocytic leukemia has a mutation in a gene of the RAS pathway.

53. The method of claim 48, wherein the patient suffering from juvenile myelomonocytic leukemia features a Monosomy 7 or chromosome 7 abnormality.

54. The method of any one of claims 1-53, wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO:

6.

55. The method of any one of claims 1-53, wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO:

8.

56. The method of any one of claims 1-55, wherein the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase ADCC activity.

57. The method of claim 56, wherein the substitution in the Fc region is S239D / I332E, wherein residue numbering is according to the EU Index.

58. The method of any one of claims 1-57, wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.

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